Hilde Loge Nilsen

Alsøe, Lene; Sarno, Antonio; Carracedo Huroz, Sergio; Domanska, Diana Ewa; Dingler, Felix; Lirussi, Lisa; Sengupta, Tanima; Tekin, Nuriye Basdag; Jobert, Laure; Alexandrov, Ludmil B.; Galashevskaya, Anastasia; Rada, Cristina; Sandve, Geir Kjetil; Rognes, Torbjørn; Krokan, Hans Einar & Nilsen, Hilde Loge (2017). Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG. Scientific Reports.  ISSN 2045-2322.  7(1) . doi:10.1038/s41598-017-07314-5

Fang, Evandro Fei; Kassahun, Henok; Croteau, Deborah L.; Scheibye-Knudsen, Morten; Marosi, Krisztina; Lu, Huiming; Shamanna, Raghavendra A.; Kalyanasundaram, Sumana; Bollineni, Ravi Chand; Wilson, Mark A.; Iser, Wendy B.; Wollman, Bradley N.; Morevati, Marya; Li, Jun; Kerr, Jesse S.; Lu, Qiping; Waltz, Tyler B.; Tian, Jane; Sinclair, David A.; Mattson, Mark P.; Nilsen, Hilde & Bohr, Vilhelm A. (2016). NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metabolism.  ISSN 1550-4131. 24(4), s 566- 581 . doi: 10.1016/j.cmet.2016.09.004

Jobert, Laure; Skjeldam, Hanne Kim; Dalhus, Bjørn; Galashevskaya, Anastasia; Vågbø, Cathrine Broberg; Bjørås, Magnar & Nilsen, Hilde (2013). The human base excision repair enzyme SMUG1 directly interacts with DKC1 and contributes to RNA quality control. Molecular Cell.  ISSN 1097-2765.  49(2), s 339- 345 . doi:10.1016/j.molcel.2012.11.010

Sengupta, Tanima; Torgersen, Maria Lyngaas; Kassahun, Henok; Vellai, Tibor; Simonsen, Anne & Nilsen, Hilde (2013). The Base Excision Repair AP-endonucleases functions in the same pathways as Mismatch Repair for Activation of Checkpoint Mediated Autophagy. Nature Communications.  ISSN 2041-1723. 4, s 2674 . doi: 10.1038/ncomms3674

Nilsen, Hilde; Rosewell, I.; Robins, P.; Skjelbred, Camilla; Andersen, Sonja; Slupphaug, Geir; Krokan, Hans Einar; Lindahl, T. & Barnes, D.E. (2000). ) Ung-deficient mice reveal a primary role of the uracil-DNA glycosylase enzyme during DNA replication.Molecular Cell.  ISSN 1097-2765.  s 1059- 1065

• Sleiman, A.; Vianna-Legros, F.; Lalanne, K.; Cardot-Martin, M.; Gaffin, J. & Heranney, C. [Show all 13 contributors for this article] (2026). Neuron irradiation of Caenorhabditis elegans by protons triggers base excision repair pathway with limited effect on behaviour. DNA Repair. ISSN 1568-7864. 166. doi: 10.1016/j.dnarep.2026.103957. Full text in Research Archive Show summary

  Proton therapy is increasingly used, due to its favourable physical properties such as the Bragg peak, which enable precise dose deposition while minimizing exposure to surrounding healthy tissues. One of the main indications for proton therapy is head and neck tumours. In addition to their therapeutic relevance, protons are also a key component of space radiation spectrum, raising concerns about their biological impact on normal tissues, particularly the central nervous system. Despite this growing concern, the effects of proton irradiation on adult post-mitotic neurons in vivo remain poorly understood. In this context, we analysed the impact of proton central nervous system micro-irradiation using the MIRCOM microbeam, in young adults of Caenorhabditis elegans, with a focus on DNA damage and behaviour. Protons induce localized oxidative DNA damage, confirmed by an increase in 8-oxoG signals within both the nuclei and cytoplasm of irradiated neurons. The biological response remained strictly confined to the targeted area; no signal propagation or damage was observed in neighbouring non-irradiated tissues. Despite molecular changes, there was no observable impact on behaviours such as motor activity, foraging, habituation, or touch-avoidance. These results suggest that proton exposure in post-mitotic neurons induces complex oxidative DNA damage and activates specific BER pathways without compromising functional behaviour or triggering systemic bystander effects. These insights are important for refining clinical radiation protection and understanding risks in space exploration.

• Hubers, Lisa Anne; Skjetne, Alexander Myhr; Luna, Luisa; Lefol, Yohan Pierre; Lund, Solveig Osnes & Wågbø, Ane Marit [Show all 15 contributors for this article] (2026). Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(17). doi: 10.1093/nar/gkag876. Full text in Research Archive Show summary

  Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1−/− cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1−/− cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.

• Suaste, Veronica; Presterud, Rebecca; Wennerström, Anna Berit; Wang, Heling; Zhang, Jianying & Lund, Solveig Osnes [Show all 16 contributors for this article] (2026). Transcriptional Profiling Shows Dampening of Interferon Gene Signatures by NAD Augmentation in Ataxia-Telangiectasia. International Journal of Molecular Sciences. ISSN 1661-6596. 27(13). doi: 10.3390/ijms27135652. Full text in Research Archive Show summary

  Ataxia-Telangiectasia (A-T) is a multisystem disorder caused by loss of A-T mutated (ATM) protein activity, characterized clinically by immunodeficiency and cerebellar ataxia. ATM is a master regulator of DNA damage responses and loss of ATM function is accompanied by persistent activation of PARP1 leading to depletion of intracellular NAD+ and dysfunction of a series of cellular signalling pathways dependent on NAD+, providing a mechanistic rationale for NAD+ augmentation therapy. We performed a clinical trial of NAD+ augmentation with nicotinamide riboside (NR) over 24 months in A-T patients where we observed improved coordination and eye movements in A-T patients. Here, by using peripheral blood mononuclear cells, we performed longitudinal transcriptome profiling to define molecular signatures of A-T and to assess pathway-level responses to NR supplementation. A-T patients exhibited reproducible transcriptomic alterations involving immune, vascular, and inflammatory pathways. NAD+ augmentation was associated with suppression of interferon response genes and modulation of networks correlated with neurological improvement. These findings establish systemic molecular signatures of A-T and identify potential blood-based biomarkers that reflect disease processes and therapeutic response, supporting the use of NAD+ augmentation as a disease-modifying strategy in A-T by dampening interferon signalling.

• Jonassen, Rune; Øverli, Øyvind; Hilland, Eva; Nilsen, Hilde; Esbensen, Qin Ying & Lirussi, Lisa [Show all 13 contributors for this article] (2026). Serotonin transporter polymorphism (5-HTTLPR) is associated with post-awakening cortisol measures in previous depression. Comprehensive Psychoneuroendocrinology. 27, p. 1–7. doi: 10.1016/j.cpnec.2026.100363. Full text in Research Archive Show summary

  Elevated cortisol levels have been linked to major depressive disorder (MDD), but cortisol dynamics vary substantially across individuals and clinical states. Genetic variation in the serotonin transporter polymorphism (5-HTTLPR) has been proposed as one contributor to differences in hypothalamic-pituitary-adrenal axis functioning. The present study examined associations between cortisol awakening measures and 5-HTTLPR genotype groups in individuals with a history of depression compared with healthy controls, and explored whether current depressive symptom severity was related to cortisol indices. A total of 108 individuals with a history of depression were genotyped and compared with 59 healthy controls. Participants completed structured diagnostic interviews and self-reported depressive symptoms. Salivary cortisol was sampled in the evening and at five consecutive timepoints after awakening (15-min intervals). Cortisol was analyzed using a linear mixed-effects model of repeated measures and by cortisol awakening response (CAR) summary indices: area under the curve with respect to ground (AUCg) and area under the curve with respect to increase (AUCi). Cortisol changed significantly over time, but there was no evidence that genotype groups differed in the overall cortisol timecourse. In CAR summary analyses, group differences were observed for AUCg, whereas AUCi did not show corresponding group differences. Regression analyses indicated that BDI-II was not associated with AUCg or AUCi after adjustment for covariates. These findings suggest that 5-HTTLPR-related differences, when present, may be more detectable in overall post-awakening cortisol output than in baseline-relative increase.

• Lagartos, Maria Jose Donate; Doncel, Beatriz Escobar; Zhang, Shi-qi; Pan, Junping; González, Noemí Villaseca & Anisimov, Aleksander [Show all 22 contributors for this article] (2026). Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD+. Brain. ISSN 0006-8950. 149(4), p. 1208–1223. doi: 10.1093/brain/awaf261. Full text in Research Archive Show summary

  Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer’s disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.

• Alsøe, Lene; Brackmann, Stephan Andreas; Liu, Yan; Wennerström, Anna Berit; Esbensen, Qin Ying & Kalyanasundaram, Sumana [Show all 10 contributors for this article] (2026). The Role of Nuclear APOBEC Enzymes in Neoplastic Progression of Ulcerative Colitis. Clinical and Experimental Gastroenterology. 19. doi: 10.2147/CEG.S588161. Full text in Research Archive Show summary

  Aberrant expression of the cytidine DNA deaminase AID in enterocytes within inflamed mucosa in ulcerative colitis (UC) patients has been proposed to be involved in progression of UC to colitis-associated colorectal cancer (CA-CRC). Here, we followed the expression of AID and other nuclear cytidine DNA deaminases of the APOBEC family through several stages of progression of UC in a CA-CRC case (UC progressor) and in a cohort of UC progressors and non-progressors. In inflamed and high-grade dysplastic mucosa, AICDA and APOBEC1 mRNAs, but not APOBEC3-family enzyme mRNAs, were overexpressed compared to non-inflamed tissue. Immunohistochemical staining did not show expression of AID or APOBEC3 enzymes in the enterocytes, neither in specimens from the CA-CRC case nor in biopsies from the progressor and non-progressor cohort. APOBEC1 was highly expressed in the enterocytes throughout the colorectum from the CA-CRC case and in most biopsies examined from the progressor and non-progressor cohort. The expression was not correlated with the histology of the mucosa or the progression status of the patients. In the CA-CRC case, we identified AID- and APOBEC3-associated mutation signatures in inflamed, high-grade dysplasia and cancer genomes. In conclusion, our findings suggest that AID or other nuclear APOBECs are unlikely to drive the progression of UC to CA-CRC late during course of UC. However, we cannot exclude the possibility that bursts of AID and nuclear APOBEC3 activity may contribute to formation of genome instability in early phases of disease development.

• Fossmark, Reidar; Hjorth-Hansen, Henrik; Lirussi, Lisa; Lüders, Torben; Visnovska, Martina & Liu, Yan [Show all 9 contributors for this article] (2026). Telomere Length in Celiac Disease in a Population-Based Cohort: A HUNT Study. Clinical and Translational Gastroenterology. 17(6). doi: 10.14309/ctg.0000000000001020. Full text in Research Archive Show summary

  INTRODUCTION: Celiac disease (CeD) occurs in genetically predisposed individuals who are exposed to dietary gluten proteins. Genome-wide association studies have found CeD to be associated with a genetic predisposition to shorter telomere length. It was therefore of interest to measure leukocyte telomere length in a large cohort of patients with CeD. METHODS: This study was population-based and included a defined cohort of patients with CeD in the Trøndelag Health Study. Leukocyte telomere length was measured by quantitative polymerase chain reaction (PCR) in patients and controls 1:2 matched for age, sex, alcohol, and tobacco use. RESULTS: The study population consisted of 58.7% women, with mean age 43 (SD 14.5) years, where half were never smokers, and the majority consumed little or no alcohol. Telomer length in 1,077 patients with CeD did not differ significantly from 2,147 matched controls, 10.39 kb (SD 2.21) vs 10.52 kb (SD 2.25), P = 0.088. In a mixed linear model, we found higher age and alcohol consumption, but not tobacco use or sex, to be associated with shorter telomere length. The telomere length did not differ between patients with newly diagnosed and known CeD. DISCUSSION: This large population-based study provides evidence that CeD is not associated with clinically meaningful telomere shortening.

• Ree, Anne Hansen; Bousquet, Paula; Visnovska, Martina; Lüders, Torben; Geisler, Benjamin Peter & Wang, Shixiong [Show all 16 contributors for this article] (2026). Exploratory biomarkers for oxaliplatin-induced nivolumab responsiveness in metastatic microsatellite-stable colorectal cancer. British Journal of Cancer. ISSN 0007-0920. 134, p. 1176–1182. doi: 10.1038/s41416-026-03357-6. Full text in Research Archive Show summary

  ABackground The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc analysis, we investigated whether tumour mutations or patients’ systemic inflammation might provide insights into responsiveness to the METIMMOX regimen. Methods Patients received either oxaliplatin-based chemotherapy (control group) or alternating two cycles each of chemotherapy and nivolumab (experimental group), with progression-free survival (PFS) as the primary endpoint. Tumour biopsies were sequenced with the TruSight Oncology 500 assay. Results The median tumour mutational burden (TMB; in mutations/megabase) was 8 (range, 1–13). The experimental-arm patients with TMB ≥9 or BRAF -V600E mutation ( n  = 17) achieved median PFS of 19.8 months (95% confidence interval, 11.3–28.3), longer ( p  = 0.0090) than experimental-arm patients with TMB < 9 not BRAF -V600E ( n  = 19) and control-arm patients with either TMB and BRAF status combination ( n  = 31). With TMB ≥9 or BRAF -V600E and normal, non-inflammatory level of C-reactive protein when starting nivolumab ( n  = 11), median PFS was 35.0 months (95% confidence interval, 6.8–63.0; p  < 0.0001). Conclusions TMB, somatic BRAF status and systemic inflammation should be prospectively investigated as practical biomarkers for predicting potential responsiveness to immune checkpoint inhibitors in metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer.

• Følling, Ivar; Selle, Maria Lie; Nilsen, Hogne Røed; Wennerström, Anna Berit; Nilsen, Hilde & Eide, Tor Jacob (2026). Distribution of glucagon-like peptide 1 receptor and insulin in phaeochromocytomas. Endocrine Connections. 15(1). doi: 10.1530/ec-25-0338. Full text in Research Archive Show summary

  Introduction Most phaeochromocytomas produce insulin, and some produce glucagon-like peptide 1 receptor (GLP-1R). In pancreatic β-cells, stimulation of GLP-1R causes insulin release. A few phaeochromocytoma patients experience hypoglycaemic attacks. Therefore, we studied the distribution of GLP-1R-containing and insulin-containing phaeochromocytoma cells and their relation. Methods In 20 phaeochromocytomas, we performed sequential double staining with anti-insulin and anti-GLP-1R antibodies and, in selected cases, staining with anti-insulin alone. We quantified tumour cells with positive staining and compared their distribution to that of randomly distributed cells using simulations. We obtained GLP-1R transcript data from 182 such tumours from The Cancer Genome Atlas (TCGA) Research Network. Results GLP-1R-containing cells were found in six of the 20 tumours, and insulin-containing cells were found in fifteen. Moreover, in the TCGA cohort, almost half of the tumours produce GLP-1R transcripts, and patients with the highest number of transcripts show longer disease-free survival. In the tumours, we found that cells expressing insulin were present in the cytoplasm and GLP-1R in the membrane, with a frequency of 2.59 and 1.34%, respectively. These cells showed clustering, and one tumour showed a large clonal expansion. Interestingly, we found deposits of insulin, which we suggest naming insulin bodies in two tumours. Very few cells contained both proteins. Conclusion Most phaeochromocytomas contain tumour cells producing insulin. About half produce GLP-1R. The producing cells show clustering, and clonal expansion occurs. Insulin release might cause hypoglycaemia. Increased GLP-1R levels might induce less aggressive tumours.

• Zhu, Hengyi; Eide, Dag Markus; Maremonti, Erica; Nilsen, Hilde & Brede, Dag Anders (2026). Mechanistic insight into the reprotoxic effects of chronic gamma radiation on spermatogenesis in Caenorhabditis elegans. Science of the Total Environment. ISSN 0048-9697. 1016. doi: 10.1016/j.scitotenv.2026.181444. Full text in Research Archive Show summary

  Ionizing radiation is a potent genotoxic agent that may cause detrimental effects on reproductive processes. This study investigated cellular events and transcriptomic alterations underlying reproductive defects caused by chronic gamma (γ) radiation in Caenorhabditis elegans (C. elegans). Continuous exposure (100 mGy/h; total dose: 4.8 Gy) throughout larval development reduced spermatid counts (38.8%) and total brood size (26.4%). It also resulted in delayed and attenuated residual body (RB) formation (22.8%), implicating reduced number of spermatocytes or failed meiosis. Targeted exposure of early L3 to L4 (24-h, total dose 2.4 Gy) after the establishment of the primary spermatocyte population resulted in 26% reduction in brood size, thus implicating damage inflicted during meiosis as detrimental to spermatogenesis. The reprotoxic defects were markedly exacerbated by rad-51 RNAi or polq-1 deletion, confirming the crucial roles for homologous recombination (HR) and polymerase theta-mediated end joining (TMEJ) in mitigating radiation-induced reproductive damage. Phenotypical investigation of the male gonad revealed genotoxic effects including shortened mitotic zone and increased cell-cycle arrest. However, the postmeiotic stage assessed as the quantity of RB-containing phagosomes remained unaffected by ionizing radiation. Transcriptomic profiling of irradiated males showed comprehensive enhanced stress response and mitophagy accompanied by alterations of energy metabolism. Comparative transcriptomic analysis revealed large differences between sexes, where the only shared enrichment term was mitochondrial translation termination. Collectively, our results show that detrimental effects to hermaphrodite spermatogenesis occur during the meiotic phase, which leads to fewer RBs and spermatids, with a corresponding reduction in reproduction.

• Arczewska, Katarzyna D; Sys, Dorota; Nilsen, Hilde L & Piekiełko-Witkowska, Agnieszka (2025). DNA Damage and Repair in Thyroid Physiology and Disease. Endocrine reviews. ISSN 0163-769X. 47(1), p. 121–157. doi: 10.1210/endrev/bnaf035. Full text in Research Archive Show summary

  The thyroid is exposed to DNA damage induced by normal physiological processes (eg, oxidative stress resulting from thyroid hormone synthesis or mitochondrial respiration) or through environmental insults (eg, environmental pollutants, ionizing radiation exposure). Robust antioxidative stress defense and DNA repair mechanisms protect thyrocyte genome integrity, but defective or dysregulated DNA repair pathways have been implicated in thyroid pathology, including autoimmune thyroid disease and thyroid malignancy. In thyroid cancer, disturbed antioxidative stress defense, Mismatch Repair, Non-Homologous End-Joining, or DNA damage response pathways contribute to both the onset and progression of the disease. The insight into mechanisms governing thyrocyte genome integrity may help to gain better understanding of the pathology and suggest novel therapeutic regimens, urgently needed in treatment-refractory disease. In the current review, we provide comprehensive description of the exogenous and endogenous factors, as well as DNA repair mechanisms influencing thyrocyte genome integrity. Moreover, we pinpoint major research avenues that should be pursued in future research. This information will be valuable in directing new discoveries to better understand thyroid disease pathomechanisms, as well as aid development of novel diagnostic and therapeutic tools.

• Bø, Ragnhild; Jonassen, Rune; Harmer, Catherine; Øverli, Øyvind; Nilsen, Hilde & Esbensen, Qin Ying [Show all 13 contributors for this article] (2025). 5-HTTLPR does not moderate the effect of attention bias modification for depression: a randomized sham-controlled trial. Translational Psychiatry. 15, p. 1–6. doi: 10.1038/s41398-025-03581-3. Full text in Research Archive Show summary

  Abstract The 5-HTTLPR polymorphism in the serotonin transporter gene SLC6A4 has previously been dubbed a plasticity marker. Within the 5-HTTLPR polymorphism, a SNP (rs25531) in the L-allele in the promoter region, affects the transcription efficacy of the SCL6A4 , leading to functionally important differences related to serotonin transporter availability in the synapses. 5-HTTLPR has been implicated in magnitude of negative attentional bias, a causal risk factor for depression, and the modifiability of attentional biases both in positive and negative directions. Hence, this genotype may moderate the outcomes of attention bias modification (ABM) targeted at reducing depressive symptoms. We conducted a registered randomized sham-controlled trial of ABM in a sample of 301 participants with a history of Major Depressive Disorder (MDD) who had residual symptoms. They were randomized and underwent 14 days of two daily session of either ABM or sham at home. Of these, 264 provided genetic samples for determining the functionally important variant of the gene SLC6A4 . We investigated if the SNP ( rs25531 ) moderated the effect of ABM on symptoms of depression (HDRS, BDI-II) and anxiety (BAI), and attention bias post-intervention. None of the outcomes were moderated by the allelic variation in the promoter region of 5-HTTLPR . Limitations include low level of depressive symptoms, lack of data on ethnicity, current and prenatal level of stress, and early traumatic experiences. The 5-HTTLPR polymorphism did not moderate the effect of ABM on the symptom scales, nor attentional bias. Combination or interactions with other genes may be required for prescribing personalized interventions.

• Rudolfova, Natalie; Skjetne, Alexander Myhr; Montaldo, Nicola Pietro; Visnes, Torkild; Nilsen, Hilde & Michel, Maurice (2025). What is in a name? Rethinking SMUG1 in genome maintenance. NAR Cancer. 7(4), p. 1–12. doi: 10.1093/narcan/zcaf050. Full text in Research Archive Show summary

  Small base lesions in DNA are primarily repaired through the base excision repair pathway, which is initiated by DNA glycosylases. This review focuses on single-strand selective monofunctional uracil–DNA glycosylase (SMUG1), an enzyme whose name incompletely captures its broader biological roles. SMUG1 excises a wide range of substrates beyond uracil, shows a preference for double-stranded DNA, and has been reported to be a bifunctional DNA glycosylase with a weak lyase activity. Moreover, SMUG1 plays roles extending beyond DNA repair, including functions in RNA quality control and RNA biogenesis. Recently, genetic interactions have been described between SMUG1 and proteins that safeguard stressed replication forks, implicating a function for SMUG1 in cancer cell biology. Understanding SMUG1’s full repertoire is key to uncovering its role in genome maintenance and unlocking its potential as a therapeutic target. Here, we review the biochemical properties reported for SMUG1 and its distinct functions from other uracil–DNA glycosylases in vivo. We also highlight the emerging role of SMUG1 in cancer cells and its potential as a therapeutic target, emphasizing the need to define the genetic and molecular contexts in which its modulation may be beneficial.

• Alsøe, Lene; Brackmann, Stephan Andreas; Lefol, Yohan Pierre; Wennerström, Anna Berit; Liu, Yan & Riques, Rosa Ana [Show all 8 contributors for this article] (2025). Colonic Mucosal Gene Expression Profile in Patients with Neoplastic Progression in Longstanding Ulcerative Colitis. Clinical and Experimental Gastroenterology. 18, p. 215–232. doi: 10.2147/ceg.s528854. Full text in Research Archive
• Anwer, Danish; Montaldo, Nicola Pietro; Novoa-del-Toro, Elva Maria; Domanska, Diana; Nilsen, Hilde Loge & Polster, Annikka Virginia (2025). Longitudinal assessment of DNA repair signature trajectory in prodromal versus established Parkinson’s disease. NPJ Parkinson's Disease. 11(1). doi: 10.1038/s41531-025-01194-7. Full text in Research Archive Show summary

  Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. DNA repair dysfunction and integrated stress response (ISR) dysregulation have been suggested to be relevant in PD pathophysiology, but their role during the prodromal phase, before motor symptoms manifest, remains unclear. In this study, we analyzed longitudinal blood transcriptomic data from the Parkinson’s Progression Markers Initiative (PPMI) to investigate how DNA repair and ISR gene expression differ across healthy individuals, prodromal PD patients, and individuals with established PD. Using logistic regression classifiers, a type of supervised machine learning model, we found that DNA repair and ISR gene expression effectively distinguished prodromal PD from healthy individuals, with classification accuracy increasing over time and peaking at later prodromal stages. In contrast, these pathways failed to differentiate established PD from healthy controls, suggesting that DNA repair and ISR dysregulation play a more distinct role early in disease progression. Gene expression variability was high in prodromal PD at baseline but reduced over time, indicating a convergence in gene expression patterns as the disease advances. Notably, 50% of DNA repair genes and 74% of ISR genes exhibited nonlinear expression patterns, with an initial increase followed by a decline. This suggests a transient adaptive response that fades out as PD progresses. Feature importance analysis identified key genes, including ERCC6, PRIMPOL, NEIL2, and NTHL1, as important predictors of prodromal PD. These findings suggest that DNA repair and ISR dysregulation contribute to early-stage PD pathology and may serve as biomarkers for early disease detection and possible treatment avenues during the prodromal phase. This study highlights the role of DNA repair and ISR pathways in the prodromal phase of PD, demonstrating their potential as early molecular indicators of disease onset. Future research should validate these findings in larger cohorts and explore their relevance for early diagnostics and intervention strategies.

• Zhang, Jianying; Wang, Heling; Lautrup, Sofie Hindkjær; Nilsen, Hilde; Treebak, Jonas T. & Watne, Leiv Otto [Show all 28 contributors for this article] (2025). Emerging strategies, applications and challenges of targeting NAD+ in the clinic. Nature Aging. 5(9), p. 1704–1731. doi: 10.1038/s43587-025-00947-6. Full text in Research Archive Show summary

  Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.

• Bordin, Diana Lilian; Lefol, Yohan Pierre; Lagartos, Maria Jose Donate; Montaldo, Nicola Pietro; Rolseth, Veslemøy & Tekin, Nuriye Basdag [Show all 18 contributors for this article] (2025). SMUG1 DNA glycosylase modulates reward behaviour through regulation of olfactory receptor gene expression. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(14). doi: 10.1093/nar/gkaf722. Full text in Research Archive
• Dragland, Jenny Sofie; Liu, Gege; Nilsen, Hilde; Böttcher, Yvonne & Wang, Junbai (2025). EpiMapper: A new tool for analyzing high-throughput sequencing from CUT&Tag. Computers in Biology and Medicine. ISSN 0010-4825. 186. doi: 10.1016/j.compbiomed.2025.109692. Full text in Research Archive Show summary

  Since the invention of next-generation sequencing, new methods have been developed to understand the regulation of gene expression through epigenetic markers. Among these, CUT&Tag (Cleavage Under Targets and Tagmentation) analysis has emerged as an efficient epigenomic profiling technique with low input requirements, high sensitivity, and low background signals. Although wet-lab techniques are available, data analysis remains challenging for scientists without expert-level computational skills. Therefore, we developed EpiMapper, a new Python package that simplifies the data analysis of CUT&Tag sequencing and similar techniques, such as ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) or ChIP-seq (chromatin immunoprecipitation [ChIP] assays with sequencing), and allows biomedical scientists to easily interpret the results. This new package includes every necessary step, from quality control to annotation and differential peak analysis. In particular, EpiMapper has improved functionality (e.g., reproducibility assessment) compared to previous analysis protocols and visualization plots and provides new features, such as genome annotation and differential peak analysis. Using three case studies, two on CUT&Tag and one on ATAC-seq data, the EpiMapper Python package successfully reproduced previous results.

• Montaldo, Nicola Pietro; Nilsen, Hilde & Bordin, Diana Lilian (2025). Targeting base excision repair in precision oncology. DNA Repair. ISSN 1568-7864. 149. doi: 10.1016/j.dnarep.2025.103844. Full text in Research Archive Show summary

  Targeting the DNA damage response (DDR) is a key strategy in cancer therapy, leveraging tumour-specific weaknesses in DNA repair pathways to enhance treatment efficacy. Traditional treatments, such as chemotherapy and radiation, use a broad, damage-inducing approach, whereas precision oncology aims to tailor therapies to specific genetic mutations or vulnerabilities. The clinical success of PARP inhibitors has renewed the interest in targeting DNA repair as a therapeutic strategy. Expanding the precision oncology toolbox by targeting the base excision repair (BER) pathway presents a promising avenue for cancer therapy, particularly in tumours that rely heavily on this pathway due to deficiencies in other DNA repair mechanisms. This review discusses how targeting BER could improve treatment outcomes, particularly in DDR-defective cancers. With ongoing advancements in biomarker discovery and drug development, BER-targeted therapies hold significant potential for refining precision oncology approaches.

• Lautrup, Sofie Hindkjær; Zhang, Shi-qi; Funayama, Shinichiro; Lirussi, Lisa; Visnovska, Martina & Cheung, Hoi-Hung [Show all 19 contributors for this article] (2025). Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation. Aging. 17(4), p. 937–959. doi: 10.18632/aging.206236. Full text in Research Archive
• Wang, Heling; Duque, Gustavo; Siow, Richard; Medina, Tomás Alejandro Schmauck; Zhang, Jianying & Sandset, Per Morten [Show all 39 contributors for this article] (2024). Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway–UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies. The journals of gerontology. Series A, Biological sciences and medical sciences. ISSN 1079-5006. 79(4). doi: 10.1093/gerona/glae029. Full text in Research Archive Show summary

  Abstract Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

• Hubers, Lisa Anne; Skjetne, Alexander Myhr; Luna, Luisa; Lefol, Yohan Pierre; Lund, Solveig Osnes & Wågbø, Ane Marit [Show all 14 contributors for this article] (2024). Functional Impact of Nth-like DNA glycosylase on Mitochondrial Dynamics. bioRxiv. ISSN 2692-8205. doi: 10.1101/2024.10.10.617535. Full text in Research Archive Show summary

  ABSTRACT NTH-like DNA glycosylase (NTHL1), a key enzyme in the base excision repair (BER) pathway, has long been considered essential for maintaining both nuclear and mitochondrial genome integrity. In this study, we integrate in vitro biochemical assays, in-cellulo molecular biology experiments, and bioinformatic analyses to investigate the impact of NTHL1 loss on mitochondrial DNA (mtDNA) stability and function. Our findings challenge the conventional view by showing that the loss of NTHL1 confers a positive phenotype. Although NTHL1 deletion in human cells results in a significant accumulation of mtDNA lesions, it is unexpectedly accompanied by a substantial increase in mtDNA copy number (CN), which correlates with elevated oxidative phosphorylation (OXPHOS) protein levels and enhanced mitochondrial respiratory capacity. Additionally, NTHL1-knockout cells exhibit larger mitochondria and increased levels of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and the membrane fusion protein Dynamin-like GTPase OPA1. These changes suggest an adaptive response to stress or altered cellular demands, aimed at enhancing mitochondrial function and capacity. Consequently, NTHL1 -knockout cells showed resistance to 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial stress along with increased phosphorylation of eIF2α. Together, this suggests that the loss of NTHL1 may enhance cellular resilience to oxidative stress by activating protective integrated stress response and mitohormesis pathways thereby contributing to cellular survival under adverse conditions. Collectively, our findings position NTHL1 as a key player in mtDNA stability and mitochondrial function, linking its DNA repair activity to the integrated stress response. Its loss triggers a shift from canonical oxidative phosphorylation to stress-adaptive pathways, ultimately enhancing cellular resistance against oxidative stress through the activation of the mitochondrial hormetic response.

• Ree, Anne Hansen; Benth, Jurate Saltyte; Hamre, Hanne Mari; Kersten, Christian; Hofsli, Eva & Guren, Marianne [Show all 14 contributors for this article] (2024). First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer—the randomised METIMMOX trial. British Journal of Cancer. ISSN 0007-0920. 130(12), p. 1921–1928. doi: 10.1038/s41416-024-02696-6. Full text in Research Archive Show summary

  Background We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. Methods Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. Results Eighty patients were randomised and 38 in each group received treatment. PFS was comparable—control group: median 9.2 months (95% confidence interval (CI), 6.3–12.7); experimental group: median 9.2 months (95% CI, 4.5–15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04–0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8–23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. Conclusions The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. Trial registration ClinicalTrials.gov number, NCT03388190 (02/01/2018).

• Romero-Aranda, Cristina; Sáenz-Narciso, Beatriz; Gómez-Orte, Eva; Metola, Ángela; Ezcurra, Begoña & Calvo, Olga [Show all 9 contributors for this article] (2024). Integrator complex subunit 6 (INTS-6) mediates DNA damage response in Caenorhabditis elegans. microPublication Biology. p. 1–8. doi: 10.17912/micropub.biology.001345. Full text in Research Archive Show summary

  The Caenorhabditis elegans Integrator complex is a set of at least 13 evolutionarily conserved proteins that binds the C-terminal domain of RNA polymerase II to regulate snRNA 3'-end processing and gene expression. Here we show that the Integrator subunit 6 intervenes in the DNA damage response in C. elegans. We find that upon X-ray radiation, INTS-6 is necessary for RAD-51 foci formation. In addition, CDK-1 Tyr-15 phosphorylation depends on the presence of INTS-6. This work adds a new piece to elucidate the Integrator complex mechanism of action in DNA repair.

• Turconi, Giorgio; Alam, Farhan; Sengupta, Tanima; Pirnes-Karhu, Sini; Olfat, Soophie & Schmidt, Mark S. [Show all 16 contributors for this article] (2024). Nicotinamide riboside first alleviates symptoms but later downregulates dopamine metabolism in proteasome inhibition mouse model of Parkinson's disease. Heliyon. 10(14), p. 1–12. doi: 10.1016/j.heliyon.2024.e34355. Full text in Research Archive Show summary

  Parkinson's disease (PD) is associated with a reduction in 26/20S proteasome and mitochondrial function and depletion of dopamine. Activation of mitochondrial function with the NAD+ precursor nicotinamide riboside (NR) is a potential therapeutic for PD. However, despite recently started clinical trials, analysis of NR in mammalian animal PD models is lacking and data in simpler PD models is limited. We analyzed the effect of NR in C. elegans and in mouse 26/20S proteasome inhibition models of PD. In C. elegans, NR rescued α-synuclein overexpression induced phenotypes likely by activating the mitochondrial unfolded protein response. However, in a proteasome inhibitor-induced mouse model of PD, NR first partially rescued behavioural dysfunction, but later resulted in decrease in dopamine and its related gene expression in the substantia nigra. Our results suggest that reduction in 26/20S function with long term NR treatment may increase risk for developing reduced nigrostriatal DA function.

• Ree, Anne Hansen; Høye, Eirik; Esbensen, Qin Ying; Beitnes, Ann-Christin Røberg; Negård, Anne & Bernklev, Linn [Show all 16 contributors for this article] (2024). Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade. Oncoimmunology. ISSN 2162-4011. 13(1). doi: 10.1080/2162402X.2024.2372886. Full text in Research Archive Show summary

  The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2–11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20–35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

• Nilsen, Hilde; Helland, Åslaug & Puco, Katarina (2024). IMPRESS-Norway: improving public cancer care by implementing precision medicine in Norway; inclusion rates and preliminary results. Acta Oncologica. ISSN 0284-186X. 63, p. 379–384. doi: 10.2340/1651-226X.2024.28322. Full text in Research Archive
• Presterud, Rebecca; Deng, Wei Hai; Wennerström, Anna Berit; Burgers, Geertruida Aleida Wilhelmina; Gajera, Bharat & Mattsson, Kirsten G. [Show all 11 contributors for this article] (2023). Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia. Movement Disorders. ISSN 0885-3185. p. 1–11. doi: 10.1002/mds.29645. Full text in Research Archive Show summary

  Background: Supplementation of nicotinamide riboside (NR) ameliorates neuropathology in animal models of ataxia telangiectasia (A-T). In humans, short-term NR supplementation showed benefits in neurological outcome. Objectives: The study aimed to investigate the safety and benefits of long-term NR supplementation in individuals with A-T. Methods: A single-arm, open-label clinical trial was performed in individuals with A-T, receiving NR over a period of 2 years. Biomarkers and clinical examinations were used to assess safety parameters. Standardized and validated neuromotor tests were used to monitor changes in neurological symptoms. Using generalized mixed models, test results were compared to expected disease progression based on historical data. Results: NAD+ concentrations increased rapidly in peripheral blood and stabilized at a higher level than baseline. NR supplementation was well tolerated for most participants. The total scores in the neuromotor test panels, as evaluated at the 18-month time point, improved for all but one participant, primarily driven by improvements in coordination subscores and eye movements. A comparison with historical data revealed that the progression of certain neuromotor symptoms was slower than anticipated. Conclusions: Long-term use of NR appears to be safe and well tolerated, and it improves motor coordination and eye movements in patients with A-T of all ages. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Misceo, Doriana; Lirussi, Lisa; Strømme, Petter; Sumathipala, Dulika Sanjeewani; Guerin, Andrea & Wolf, Nicole I [Show all 14 contributors for this article] (2023). A homozygous POLR1A variant causes leukodystrophy and affects protein homeostasis. Brain. ISSN 0006-8950. 146(8), p. 3513–3527. doi: 10.1093/brain/awad086. Full text in Research Archive Show summary

  Abstract RNA polymerase I transcribes ribosomal DNA to produce precursor 47S rRNA. Post-transcriptional processing of this rRNA generates mature 28S, 18S and 5.8S rRNAs, which form the ribosomes, together with 5S rRNA, assembly factors and ribosomal proteins. We previously reported a homozygous variant in the catalytic subunit of RNA polymerase I, POLR1A, in two brothers with leukodystrophy and progressive course. However, the disease mechanism remained unknown. In this report, we describe another missense variant POLR1A NM_015425.3:c.1925C&amp;gt;A; p.(Thr642Asn) in homozygosity in two unrelated patients. Patient 1 was a 16-year-old male and Patient 2 was a 2-year-old female. Both patients manifested neurological deficits, with brain MRIs showing hypomyelinating leukodystrophy and cerebellar atrophy; and in Patient 1 additionally with hypointensity of globi pallidi and small volume of the basal ganglia. Patient 1 had progressive disease course, leading to death at the age of 16.5 years. Extensive in vitro experiments in fibroblasts from Patient 1 documented that the mutated POLR1A led to aberrant rRNA processing and degradation, and abnormal nucleolar homeostasis. Proteomics data analyses and further in vitro experiments documented abnormal protein homeostasis, and endoplasmic reticulum stress responses. We confirm that POLR1A biallelic variants cause neurodegenerative disease, expand the knowledge of the clinical phenotype of the disorder, and provide evidence for possible pathological mechanisms leading to POLR1A-related leukodystrophy.

• Sleiman, Ahmad; Lalanne, Kévin; Vianna, François; Perrot, Yann; Richaud, Myriam & Sengupta, Tanima [Show all 12 contributors for this article] (2023). Targeted Central Nervous System Irradiation with Proton Microbeam Induces Mitochondrial Changes in Caenorhabditis elegans. Biology (Basel). 12(6). doi: 10.3390/biology12060839. Full text in Research Archive
• Kalyanasundaram, Sumana; Lefol, Yohan Pierre; Gundersen, Sveinung; Rognes, Torbjørn; Alsøe, Lene & Nilsen, Hilde [Show all 9 contributors for this article] (2023). hGSuite HyperBrowser: A web-based toolkit for hierarchical metadata-informed analysis of genomic tracks. PLOS ONE. 18(7). doi: 10.1371/journal.pone.0286330. Full text in Research Archive Show summary

  Many high-throughput sequencing datasets can be represented as objects with coordinates along a reference genome. Currently, biological investigations often involve a large number of such datasets, for example representing different cell types or epigenetic factors. Drawing overall conclusions from a large collection of results for individual datasets may be challenging and time-consuming. Meaningful interpretation often requires the results to be aggregated according to metadata that represents biological characteristics of interest. In this light, we here propose the hierarchical Genomic Suite HyperBrowser (hGSuite), an open-source extension to the GSuite HyperBrowser platform, which aims to provide a means for extracting key results from an aggregated collection of high-throughput DNA sequencing data. The hGSuite utilizes a metadata-informed data cube to calculate various statistics across the multiple dimensions of the datasets. With this work, we show that the hGSuite and its associated data cube methodology offers a quick and accessible way for exploratory analysis of large genomic datasets. The web-based toolkit named hGsuite Hyperbrowser is available at https://hyperbrowser.uio.no/hgsuite under a GPLv3 license.

• Qian, Shuangjie; He, Haijun; Xiong, Xi; Ai, Ruixue; Wang, Wenwen & Zhu, Huimin [Show all 10 contributors for this article] (2023). Identification of mitophagy-associated proteins profile as potential plasma biomarkers of idiopathic Parkinson's disease. CNS Neuroscience & Therapeutics. ISSN 1755-5930. 00, p. 1–14. doi: 10.1111/cns.14532. Full text in Research Archive Show summary

  Abstract Background Despite extensive work to identify diagnostic plasma markers for Parkinson's disease (PD), there are still no accepted and validated surrogate biomarkers. Mitophagy‐associated proteins (MAPs), including PTEN‐induced putative kinase 1 (PINK1), Parkin, phosphoglycerate mutase 5 (PGAM5), BCL2 interacting protein 3 (BNIP3), and phosphorylated‐TBK1 (p‐TBK1), are, to our best knowledge, not well studied as a panel of biomarkers of neurodegeneration in PD. Methods The study population comprised 116 age‐matched controls (HC), 179 PD patients, alongside and 90 PD syndromes (PDs) divided between two cohorts: (i) the modeling cohort (cohort 1), including 150 PD, 97 HC, and 80 PDs; and (ii) the validated cohort (cohort 2), including 29 PD, 19 HC, and 10 PDs. Results MAPs are elevated in the plasma of PD patients. PINK1, Parkin, and PGAM5 displayed the top three measurable increase trends in amplitude compared to BNIP3 and p‐TBK1. Moreover, the area under the curve (AUC) values of PINK1, PGAM5, and Parkin were ranked the top three MAP candidates in diagnosis accuracy for PD from HC, but the MAPs make it hard to differentiate PD from PDs. In addition, there are higher plasma PINK1‐Parkin levels and prominent diagnostic accuracy in A‐synuclein (+) subjects than in A‐synuclein (−) subjects. Conclusions These results uncover that plasma MAPs (PINK1, Parkin, and PGAM5) may be potentially useful diagnostic biomarkers for PD diagnosis. Studies on larger cohorts would be required to test whether elevated plasma MAP levels are related to PD risk or prognosis.

• Prebensen, Christian Haugland; Lefol, Yohan Pierre; Myhre, Peder Langeland; Lüders, Torben; Jonassen, Christine M & Blomfeldt, Anita [Show all 9 contributors for this article] (2023). Longitudinal whole blood transcriptomic analysis characterizes neutrophil activation and interferon signaling in moderate and severe COVID-19. Scientific Reports. 13(1). doi: 10.1038/s41598-023-37606-y. Full text in Research Archive Show summary

  Abstract A maladaptive inflammatory response has been implicated in the pathogenesis of severe COVID-19. This study aimed to characterize the temporal dynamics of this response and investigate whether severe disease is associated with distinct gene expression patterns. We performed microarray analysis of serial whole blood RNA samples from 17 patients with severe COVID-19, 15 patients with moderate disease and 11 healthy controls. All study subjects were unvaccinated. We assessed whole blood gene expression patterns by differential gene expression analysis, gene set enrichment, two clustering methods and estimated relative leukocyte abundance using CIBERSORT. Neutrophils, platelets, cytokine signaling, and the coagulation system were activated in COVID-19, and this broad immune activation was more pronounced in severe vs. moderate disease. We observed two different trajectories of neutrophil-associated genes, indicating the emergence of a more immature neutrophil phenotype over time. Interferon-associated genes were strongly enriched in early COVID-19 before falling markedly, with modest severity-associated differences in trajectory. In conclusion, COVID-19 necessitating hospitalization is associated with a broad inflammatory response, which is more pronounced in severe disease. Our data suggest a progressively more immature circulating neutrophil phenotype over time. Interferon signaling is enriched in COVID-19 but does not seem to drive severe disease.

• Lirussi, Lisa & Nilsen, Hilde (2023). DNA Glycosylases Define the Outcome of Endogenous Base Modifications. International Journal of Molecular Sciences. ISSN 1661-6596. 24(12), p. 1–19. doi: 10.3390/ijms241210307. Full text in Research Archive Show summary

  Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell fate by regulating chromatin organisation and gene expression. Identical chemical modifications exerting different functions pose a challenge for the cell’s DNA repair machinery, as it needs to accurately distinguish between epigenetic marks and DNA damage to ensure proper repair and maintenance of (epi)genomic integrity. The specificity and selectivity of the recognition of these modified bases relies on DNA glycosylases, which acts as DNA damage, or more correctly, as modified bases sensors for the base excision repair (BER) pathway. Here, we will illustrate this duality by summarizing the role of uracil-DNA glycosylases, with particular attention to SMUG1, in the regulation of the epigenetic landscape as active regulators of gene expression and chromatin remodelling. We will also describe how epigenetic marks, with a special focus on 5-hydroxymethyluracil, can affect the damage susceptibility of nucleic acids and conversely how DNA damage can induce changes in the epigenetic landscape by altering the pattern of DNA methylation and chromatin structure.

• Lefol, Yohan Pierre; Korfage, Tom; Mjelle, Robin; Prebensen, Christian Haugland; Lüders, Torben & Müller, Bruno [Show all 13 contributors for this article] (2023). TiSA: TimeSeriesAnalysis - A pipeline for the analysis of longitudinal transcriptomics data. NAR Genomics and Bioinformatics. 5(1). doi: 10.1093/nargab/lqad020. Full text in Research Archive Show summary

  Improved transcriptomic sequencing technologies now make it possible to perform longitudinal experiments, thus generating a large amount of data. Currently, there are no dedicated or comprehensive methods for the analysis of these experiments. In this article, we describe our TimeSeries Analysis pipeline (TiSA) which combines differential gene expression, clustering based on recursive thresholding, and a functional enrichment analysis. Differential gene expression is performed for both the temporal and conditional axes. Clustering is performed on the identified differentially expressed genes, with each cluster being evaluated using a functional enrichment analysis. We show that TiSA can be used to analyse longitudinal transcriptomic data from both microarrays and RNA-seq, as well as small, large, and/or datasets with missing data points. The tested datasets ranged in complexity, some originating from cell lines while another was from a longitudinal experiment of severity in COVID-19 patients. We have also included custom figures to aid with the biological interpretation of the data, these plots include Principal Component Analyses, Multi Dimensional Scaling plots, functional enrichment dotplots, trajectory plots, and complex heatmaps showing the broad overview of results. To date, TiSA is the first pipeline to provide an easy solution to the analysis of longitudinal transcriptomics experiments.

• Durfee, Cameron; Temiz, Nuri Alpay; Levin-Klein, Rena; Argyris, Prokopios P.; Alsøe, Lene & Huroz, Sergio Carracedo [Show all 16 contributors for this article] (2023). Human APOBEC3B promotes tumor development in vivo including signature mutations and metastases. Cell Reports Medicine. 4(10), p. 1–26. doi: 10.1016/j.xcrm.2023.101211. Full text in Research Archive Show summary

  The antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many cancers. However, despite years of work, a causal relationship has yet to be established in vivo. Here, we report a murine model that expresses tumor-like levels of human APOBEC3B. Animals expressing full-body APOBEC3B appear to develop normally. However, adult males manifest infertility, and older animals of both sexes show accelerated rates of carcinogenesis, visual and molecular tumor heterogeneity, and metastasis. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Enrichment for APOBEC3B-attributable single base substitution mutations also associates with elevated levels of insertion-deletion mutations and structural variations. APOBEC3B catalytic activity is required for all of these phenotypes. Together, these studies provide a cause-and-effect demonstration that human APOBEC3B is capable of driving both tumor initiation and evolution in vivo.

• Høyer, Helle; Busk, Øyvind Løvold; Esbensen, Qin Ying; Røsby, Oddveig; Hilmarsen, Hilde Tveitan & Russell, Michael Bjørn [Show all 9 contributors for this article] (2022). Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation. BMC Neurology. 22(1). doi: 10.1186/s12883-022-02828-6. Full text in Research Archive Show summary

  Background: Aminoacyl tRNA-synthetases are ubiquitously-expressed enzymes that attach amino acids to their cognate tRNA molecules. Mutations in several genes encoding aminoacyl tRNA-synthetases, have been associated with peripheral neuropathy, i.e. AARS1, GARS1, HARS1, YARS1 and WARS1. The pathogenic mechanism underlying AARS1-related neuropathy is not known. Methods: From 2012 onward, all probands presenting at Telemark Hospital (Skien, Norway) with peripheral neuropathy were screened for variants in AARS1 using an "in-house" next-generation sequencing panel. DNA from patient's family members was examined by Sanger sequencing. Blood from affected family members and healthy controls were used for quantification of AARS1 mRNA and alanine. Proteomic analyses were conducted in peripheral blood mononuclear cells (PBMC) from four affected family members and five healthy controls. Results: Seventeen individuals in two Norwegian families affected by Charcot-Marie-Tooth disease (CMT) were characterized in this study. The heterozygous NM_001605.2:c.976C > T p.(Arg326Trp) AARS1 mutation was identified in ten affected family members. All living carriers had a mild to severe length-dependent sensorimotor neuropathy. Three deceased obligate carriers aged 74-98 were reported to be unaffected, but were not examined in the clinic. Proteomic studies in PBMC from four affected individuals suggest an effect on the immune system mediated by components of a systemic response to chronic injury and inflammation. Furthermore, altered expression of proteins linked to mitochondrial function/dysfunction was observed. Proteomic data are available via ProteomeXchange using identifier PXD023842. Conclusion: This study describes clinical and neurophysiological features linked to the p.(Arg326Trp) variant of AARS1 in CMT-affected members of two Norwegian families. Proteomic analyses based on of PBMC from four CMT-affected individuals suggest that involvement of inflammation and mitochondrial dysfunction might contribute to AARS1 variant-associated peripheral neuropathy.

• Huroz, Sergio Carracedo; Lirussi, Lisa; Alsøe, Lene; Segers, Filip; Wang, Changliang & Bartosova, Zdenka [Show all 21 contributors for this article] (2022). SMUG1 regulates fat homeostasis leading to a fatty liver phenotype in mice. DNA Repair. ISSN 1568-7864. 120. doi: 10.1016/j.dnarep.2022.103410. Full text in Research Archive
• Sengupta, Tanima; Lefol, Yohan Pierre; Lirussi, Lisa; Morales, Veronica Suaste; Lüders, Torben & Gupta, Swapnil [Show all 10 contributors for this article] (2022). Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging. Aging. 14(21), p. 8661–8687. doi: 10.18632/aging.204375. Full text in Research Archive Show summary

  There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in long-chain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.

• Lirussi, Lisa; Ayyildiz, Dilara; Liu, Yan; Montaldo, Nicola Pietro; Huroz, Sergio Carracedo & Aure, Miriam Ragle [Show all 16 contributors for this article] (2022). A regulatory network comprising let-7 miRNA and SMUG1 is associated with good prognosis in ER+ breast tumours. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(18), p. 10449–10468. doi: 10.1093/nar/gkac807. Full text in Research Archive Show summary

  Abstract Single-strand selective uracil–DNA glycosylase 1 (SMUG1) initiates base excision repair (BER) of uracil and oxidized pyrimidines. SMUG1 status has been associated with cancer risk and therapeutic response in breast carcinomas and other cancer types. However, SMUG1 is a multifunctional protein involved, not only, in BER but also in RNA quality control, and its function in cancer cells is unclear. Here we identify several novel SMUG1 interaction partners that functions in many biological processes relevant for cancer development and treatment response. Based on this, we hypothesized that the dominating function of SMUG1 in cancer might be ascribed to functions other than BER. We define a bad prognosis signature for SMUG1 by mapping out the SMUG1 interaction network and found that high expression of genes in the bad prognosis network correlated with lower survival probability in ER+ breast cancer. Interestingly, we identified hsa-let-7b-5p microRNA as an upstream regulator of the SMUG1 interactome. Expression of SMUG1 and hsa-let-7b-5p were negatively correlated in breast cancer and we found an inhibitory auto-regulatory loop between SMUG1 and hsa-let-7b-5p in the MCF7 breast cancer cells. We conclude that SMUG1 functions in a gene regulatory network that influence the survival and treatment response in several cancers.

• Karlsen, Tom Rune; Olsen, Maria Belland; Kong, Xiang Yi; Yang, Kuan; Quiles-Jiménez, Ana M T & Kroustallaki, Pinelopi [Show all 15 contributors for this article] (2022). NEIL3-deficient bone marrow displays decreased hematopoietic capacity and reduced telomere length. Biochemistry and Biophysics Reports. 29. doi: 10.1016/j.bbrep.2022.101211. Full text in Research Archive Show summary

  Deficiency of NEIL3, a DNA repair enzyme, has significant impact on mouse physiology, including vascular biology and gut health, processes related to aging. Leukocyte telomere length (LTL) is suggested as a marker of biological aging, and shortened LTL is associated with increased risk of cardiovascular disease. NEIL3 has been shown to repair DNA damage in telomere regions in vitro. Herein, we explored the role of NEIL3 in telomere maintenance in vivo by studying bone marrow cells from atherosclerosis-prone NEIL3-deficient mice. We found shortened telomeres and decreased activity of the telomerase enzyme in bone marrow cells derived from Apoe−/−Neil3−/− as compared to Apoe−/− mice. Furthermore, Apoe−/−Neil3−/− mice had decreased leukocyte levels as compared to Apoe−/− mice, both in bone marrow and in peripheral blood. Finally, RNA sequencing of bone marrow cells from Apoe−/−Neil3−/− and Apoe−/− mice revealed different expression levels of genes involved in cell cycle regulation, cellular senescence and telomere protection. This study points to NEIL3 as a telomere-protecting protein in murine bone marrow in vivo.

• Xie, Chenglong; Zhuang, Xu-Xu; Niu, Zhangming; Ai, Ruixue; Lautrup, Sofie Hindkjær & Zheng, Shuangjia [Show all 29 contributors for this article] (2022). Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow. Nature Biomedical Engineering. 6(1), p. 76–93. doi: 10.1038/s41551-021-00819-5. Full text in Research Archive Show summary

  Abstract A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

• Akbari, Mansour; Nilsen, Hilde & Montaldo, Nicola Pietro (2022). Dynamic features of human mitochondrial DNA maintenance and transcription. Frontiers in Cell and Developmental Biology. 10. doi: 10.3389/fcell.2022.984245. Full text in Research Archive Show summary

  Mitochondria are the primary sites for cellular energy production and are required for many essential cellular processes. Mitochondrial DNA (mtDNA) is a 16.6 kb circular DNA molecule that encodes only 13 gene products of the approximately 90 different proteins of the respiratory chain complexes and an estimated 1,200 mitochondrial proteins. MtDNA is, however, crucial for organismal development, normal function, and survival. MtDNA maintenance requires mitochondrially targeted nuclear DNA repair enzymes, a mtDNA replisome that is unique to mitochondria, and systems that control mitochondrial morphology and quality control. Here, we provide an overview of the current literature on mtDNA repair and transcription machineries and discuss how dynamic functional interactions between the components of these systems regulate mtDNA maintenance and transcription. A profound understanding of the molecular mechanisms that control mtDNA maintenance and transcription is important as loss of mtDNA integrity is implicated in normal process of aging, inflammation, and the etiology and pathogenesis of a number of diseases.

• Vatn, Simen Svendsen; Lindstrøm, Jonas Christoffer; Moen, Aina Elisabeth Fossum; Brackmann, Stephan Andreas; Tannæs, Tone Møller & Olbjørn, Christine [Show all 19 contributors for this article] (2022). Mucosal Gene Transcript Signatures in Treatment Naïve Inflammatory Bowel Disease: A Comparative Analysis of Disease to Symptomatic and Healthy Controls in the European IBD-Character Cohort. Clinical and Experimental Gastroenterology. 15, p. 5–25. doi: 10.2147/CEG.S343468. Full text in Research Archive Show summary

  Background: Studies of the mucosal transcriptomic landscape have given new insight into the pathogenesis of inflammatory bowel disease (IBD). Recently, the predictive biomarker potential of gene expression signatures has been explored. To further investigate the mucosal gene expression in IBD, we recruited a cohort of treatment naïve patients and compared them to both symptomatic and healthy controls. Methods: Altogether, 323 subjects were included: Crohn’s disease (N = 75), ulcerative colitis (N = 87) and IBD unclassified (N = 3). Additionally, there were two control groups: symptomatic controls (N = 131) and healthy controls (N = 27). Mucosal biopsies were collected during ileocolonoscopy and gene expression in inflamed and non-inflamed mucosa was explored. Gene expression profiling was performed using Agilent G3 Human Gene Expression 860K v3 One-Color microarray. We recorded information about treatment escalation to anti-TNF agents or surgery, and anti-TNF response, to explore predictive opportunities of the mucosal transcriptome. Results: Gene expression profiles in symptomatic controls in whom IBD had been excluded resembled that of IBD patients and diverged from that of healthy controls. In non-inflamed Crohn’s disease and ulcerative colitis, gene set enrichment analysis revealed dysregulation of pathways involved in basic cellular biological processes. Mitochondria-associated pathways were dysregulated both in non-inflamed and inflamed Crohn’s disease and ulcerative colitis (> 2.6 normalized enrichment scores <− 1.8). Gene expression signatures of Crohn’s disease and ulcerative colitis did not predict time for treatment escalation (p = 0.175). No significant association was found between gene expression signatures and anti-TNF response. Conclusion: Non-inflamed samples are probably superior to inflamed samples when exploring gene expression signatures in IBD and might reveal underlying mechanisms central for disease initiation. The gene expression signatures of the control groups were related to if they were symptomatic or not, which may have important implications for future study designs.

• Sumathipala, Dulika Sanjeewani; Strømme, Petter; Fattahi, Zohreh; Lüders, Torben; Sheng, Ying & Kahrizi, Kimia [Show all 20 contributors for this article] (2022). ZBTB11 dysfunction: Spectrum of brain abnormalities, biochemical signature and cellular consequences. Brain. ISSN 0006-8950. 145(7), p. 2602–2616. doi: 10.1093/brain/awac034. Full text in Research Archive Show summary

  Abstract Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation–sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation–sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.

• Naranjo-Galindo, Francisco José; Ai, Ruixue; Fang, Evandro Fei; Nilsen, Hilde Loge & SenGupta, Tanima (2022). C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration. Frontiers in Aging. 3. doi: 10.3389/fragi.2022.916118. Full text in Research Archive Show summary

  Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.

• SenGupta, Tanima; Palikaras, Konstantinos; Esbensen, Qin Ying; Konstantinidis, Georgios; Galindo, Francisco Jose Naranjo & Achanta, Kavya [Show all 14 contributors for this article] (2021). Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology. Cell reports. 36(10), p. 1–44. doi: 10.1016/j.celrep.2021.109668. Full text in Research Archive Show summary

  Aging, genomic stress, and mitochondrial dysfunction are risk factors for neurodegenerative pathologies, such as Parkinson disease (PD). Although genomic instability is associated with aging and mitochondrial impairment, the underlying mechanisms are poorly understood. Here, we show that base excision repair generates genomic stress, promoting age-related neurodegeneration in a Caenorhabditis elegans PD model. A physiological level of NTH-1 DNA glycosylase mediates mitochondrial and nuclear genomic instability, which promote degeneration of dopaminergic neurons in older nematodes. Conversely, NTH-1 deficiency protects against α-synuclein-induced neurotoxicity, maintaining neuronal function with age. This apparent paradox is caused by modulation of mitochondrial transcription in NTH-1-deficient cells, and this modulation activates LMD-3, JNK-1, and SKN-1 and induces mitohormesis. The dependance of neuroprotection on mitochondrial transcription highlights the integration of BER and transcription regulation during physiological aging. Finally, whole-exome sequencing of genomic DNA from patients with idiopathic PD suggests that base excision repair might modulate susceptibility to PD in humans.

• Gupta, Swapnil; You, Panpan; Sengupta, Tanima; Nilsen, Hilde & Sharma, Kulbhushan (2021). Crosstalk between Different DNA repair pathways contributes to neurodegenerative diseases. Biology (Basel). 10(2). doi: 10.3390/biology10020163. Full text in Research Archive Show summary

  Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

• Følling, Ivar; Wennerström, Anna Berit; Eide, Tor Jacob & Nilsen, Hilde Loge (2021). Phaeochromocytomas overexpress insulin transcript and produce insulin. Endocrine Connections. 10(8), p. 815–824. doi: 10.1530/EC-21-0269. Full text in Research Archive Show summary

  Introduction Phaeochromocytomas are tumours originating in the medulla of the adrenal gland. They produce catecholamines, and some tumours also produce ectopic hormones. Two types of glucose imbalances occur in phaeochromocytoma patients, hyperglycaemia and hypoglycaemic attacks. Therefore, we tested whether insulin transcript ( INS ), insulin, and a hybrid read-through transcript between exons from insulin and insulin-like growth factor 2 ( INS-IGF2 ) were expressed in phaeochromocytomas. Methods We measured the expression of insulin using immunohistochemistry. The expression of INS-IGF2 was determined by qRT-PCR in formalin-fixed and paraffin-embedded tissue from 20 phaeochromocytomas. The expression of INS and INS-IGF2 transcriptswas also analysed in 182 phaeochromocytomas and paragangliomas using publicly available datasets in The Cancer Genome Atlas (TCGA) Database. Results Of 20 phaeochromocytomas, 16 stained positive for insulin. The distribution of positive cells was mostly scattered, with some focal expression indicating clonal expansion. Nineteen tumours expressed high levels of INS and INS-IGF2 transcripts. The expression of the two transcripts corresponded closely. In the TCGA dataset, phaeochromocytoma expresses higher levels of INS and INS-IGF2 transcripts compared to the normal non-tumour adrenal glands. Thus, the expression of INS and INS-IGF2 seems to be a general phenomenon in phaeochromocytoma. Conclusion Most phaeochromocytomas contain cells that overexpress INS and INS-IGF2 transcripts. Most tumours also display heterogeneous expression of polypeptides immunoreactive to monoclonal anti-insulin antibodies. Clinically this may relate to both hyperglycaemia and hypoglycaemic attacks seen in patients with phaeochromocytoma as well as autocrine tumour growth.

• Lirussi, Lisa; Demir, Özlem; You, Panpan; Sarno, Antonio; Amaro, Rommie E. & Nilsen, Hilde (2021). RNA metabolism guided by RNA modifications: The role of SMUG1 in rRNA quality control. Biomolecules. 11(1), p. 1–22. doi: 10.3390/biom11010076. Full text in Research Archive Show summary

  RNA modifications are essential for proper RNA processing, quality control, and maturation steps. In the last decade, some eukaryotic DNA repair enzymes have been shown to have an ability to recognize and process modified RNA substrates and thereby contribute to RNA surveillance. Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) is a base excision repair enzyme that not only recognizes and removes uracil and oxidized pyrimidines from DNA but is also able to process modified RNA substrates. SMUG1 interacts with the pseudouridine synthase dyskerin (DKC1), an enzyme essential for the correct assembly of small nucleolar ribonucleoproteins (snRNPs) and ribosomal RNA (rRNA) processing. Here, we review rRNA modifications and RNA quality control mechanisms in general and discuss the specific function of SMUG1 in rRNA metabolism. Cells lacking SMUG1 have elevated levels of immature rRNA molecules and accumulation of 5-hydroxymethyluridine (5hmU) in mature rRNA. SMUG1 may be required for post-transcriptional regulation and quality control of rRNAs, partly by regulating rRNA and stability.

• Quiles-Jiménez, Ana M T; Gregersen, Ida; Segers, Filip; Skarpengland, Tonje; Kroustallaki, Pinelopi & Yang, Kuan [Show all 30 contributors for this article] (2021). DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development. Atherosclerosis. ISSN 0021-9150. 324, p. 123–132. doi: 10.1016/j.atherosclerosis.2021.02.023. Full text in Research Archive Show summary

  Background and aims Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. Methods Chow diet-fed atherosclerosis-prone Apoe−/− mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. Results We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. Conclusions Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.

• Bordin, Diana Lilian; Lirussi, Lisa & Nilsen, Hilde (2021). Cellular response to endogenous DNA damage: DNA base modifications in gene expression regulation. DNA Repair. ISSN 1568-7864. 99, p. 1–11. doi: 10.1016/j.dnarep.2021.103051. Full text in Research Archive
• Alexeeva, Marina; Moen, Marivi Nabong; Xu, Xiang Ming; Rasmussen, Anette; Leiros, Ingar & Kirpekar, Finn [Show all 10 contributors for this article] (2021). Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification. Frontiers in Immunology. 12, p. 13–13. doi: 10.3389/fimmu.2021.762032. Full text in Research Archive Show summary

  Uracil arises in cellular DNA by cytosine (C) deamination and erroneous replicative incorporation of deoxyuridine monophosphate opposite adenine. The former generates C ! thymine transition mutations if uracil is not removed by uracil-DNA glycosylase (UDG) and replaced by C by the base excision repair (BER) pathway. The primary human UDG is hUNG. During immunoglobulin gene diversification in activated B cells, targeted cytosine deamination by activation-induced cytidine deaminase followed by uracil excision by hUNG is important for class switch recombination (CSR) and somatic hypermutation by providing the substrate for DNA double-strand breaks and mutagenesis, respectively. However, considerable uncertainty remains regarding the mechanisms leading to DNA incision following uracil excision: based on the general BER scheme, apurinic/apyrimidinic (AP) endonuclease (APE1 and/or APE2) is believed to generate the strand break by incising the AP site generated by hUNG. We report here that hUNG may incise the DNA backbone subsequent to uracil excision resulting in a 3´-a,b-unsaturated aldehyde designated uracil-DNA incision product (UIP), and a 5´-phosphate. The formation of UIP accords with an elimination (E2) reaction where deprotonation of C2´ occurs via the formation of a C1´ enolate intermediate. UIP is removed from the 3´-end by hAPE1. This shows that the first two steps in uracil BER can be performed by hUNG, which might explain the significant residual CSR activity in cells deficient in APE1 and APE2.

• Aman, Yahyah; Frank, Johannes; Lautrup, Sofie Hindkjær; Matysek, Adrian; Niu, Zhangming & Yang, Guang [Show all 13 contributors for this article] (2020). The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications. Mechanisms of Ageing and Development. ISSN 0047-6374. 185, p. 1–11. doi: 10.1016/j.mad.2019.111194. Full text in Research Archive Show summary

  Nicotinamide adenine dinucleotide (NAD+) is an important natural molecule involved in fundamental biological processes, including the TCA cycle, OXPHOS, β-oxidation, and is a co-factor for proteins promoting healthy longevity. NAD+ depletion is associated with the hallmarks of ageing and may contribute to a wide range of age-related diseases including metabolic disorders, cancer, and neurodegenerative diseases. One of the central pathways by which NAD+ promotes healthy ageing is through regulation of mitochondrial homeostasis via mitochondrial biogenesis and the clearance of damaged mitochondria via mitophagy. Here, we highlight the contribution of the NAD+-mitophagy axis to ageing and age-related diseases, and evaluate how boosting NAD+ levels may emerge as a promising therapeutic strategy to counter ageing as well as neurodegenerative diseases including Alzheimer’s disease. The potential use of artificial intelligence to understand the roles and molecular mechanisms of the NAD+-mitophagy axis in ageing is discussed, including possible applications in drug target identification and validation, compound screening and lead compound discovery, biomarker development, as well as efficacy and safety assessment. Advances in our understanding of the molecular and cellular roles of NAD+ in mitophagy will lead to novel approaches for facilitating healthy mitochondrial homoeostasis that may serve as a promising therapeutic strategy to counter ageing-associated pathologies and/or accelerated ageing.

• Brorson, Ina Skaara; Eriksson, Anna Maria; Leikfoss, Ingvild Sørum; Vitelli, Valeria; Celius, Elisabeth Gulowsen & Luders, Torben [Show all 10 contributors for this article] (2020). CD8 + T cell gene expression analysis identifies differentially expressed genes between multiple sclerosis patients and healthy controls. Multiple Sclerosis Journal, Experimental, Translational and Clinical. doi: 10.1177/2055217320978511. Full text in Research Archive Show summary

  Background: Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. Objectives: Analysis of the gene expression profiles of circulating CD8þ T cells of MS patients compared to healthy controls. Methods: RNA from purified CD8þ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. Results: We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. Conclusions: CD8þ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8þ T cells and subtypes of these may increase understanding of how T cells are involved in MS.

• Safavi, Shiva; Larouche, Ariane; Zahn, Astrid; Patenaude, Anne-Marie; Domanska, Diana Ewa & Dionne, Kiersten [Show all 17 contributors for this article] (2020). The uracil-DNA glycosylase UNG protects the fitness of normal and cancer B cells expressing AID. NAR Cancer. 2(3). doi: 10.1093/narcan/zcaa019. Full text in Research Archive Show summary

  Abstract In B lymphocytes, the uracil N-glycosylase (UNG) excises genomic uracils made by activation-induced deaminase (AID), thus underpinning antibody gene diversification and oncogenic chromosomal translocations, but also initiating faithful DNA repair. Ung−/− mice develop B-cell lymphoma (BCL). However, since UNG has anti- and pro-oncogenic activities, its tumor suppressor relevance is unclear. Moreover, how the constant DNA damage and repair caused by the AID and UNG interplay affects B-cell fitness and thereby the dynamics of cell populations in vivo is unknown. Here, we show that UNG specifically protects the fitness of germinal center B cells, which express AID, and not of any other B-cell subset, coincident with AID-induced telomere damage activating p53-dependent checkpoints. Consistent with AID expression being detrimental in UNG-deficient B cells, Ung−/− mice develop BCL originating from activated B cells but lose AID expression in the established tumor. Accordingly, we find that UNG is rarely lost in human BCL. The fitness preservation activity of UNG contingent to AID expression was confirmed in a B-cell leukemia model. Hence, UNG, typically considered a tumor suppressor, acquires tumor-enabling activity in cancer cell populations that express AID by protecting cell fitness.

• Gilmour, Brian Christopher; Gudmundsrud, Ruben; Frank, Johannes; Hov, Amund; Lautrup, Sofie Hindkjær & Aman, Yahyah [Show all 18 contributors for this article] (2020). Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing. Mechanisms of Ageing and Development. ISSN 0047-6374. 186, p. 1–6. doi: 10.1016/j.mad.2020.111208. Full text in Research Archive Show summary

  Nicotinamide adenine dinucleotide (NAD+) plays a fundamental role in life and health through the regulation of energy biogenesis, redox homeostasis, cell metabolism, and the arbitration of cell survival via linkages to apoptosis and autophagic pathways. The importance of NAD+ in ageing and healthy longevity has been revealed from laboratory animal studies and early-stage clinical testing. While basic researchers and clinicians have investigated the molecular mechanisms and translation potential of NAD+, there are still major gaps in applying laboratory science to design the most effective trials. This mini-review was based on the programme and discussions of the 3rd NO-Age Symposium held at the Akershus University Hospital, Norway on the 28th October 2019. This symposium brought together leading basic researchers on NAD+ and clinicians who are leading or are going to perform NAD+ augmentation-related clinical studies. This meeting covered talks about NAD+ synthetic pathways, subcellular homeostasis of NAD+, the benefits of NAD+ augmentation from maternal milk to offspring, current clinical trials of the NAD+ precursor nicotinamide riboside (NR) on Ataxia-Telangiectasia (A-T), Parkinson’s disease (PD), post-sepsis fatigue, as well as other potential NR-based clinical trials. Importantly, a consensus is emerging with respect to the design of clinical trials in order to measure meaningful parameters and ensure safety.

• Nguyen, Chinh BKrong; Kumar, Surendra; Zucknick, Manuela; Kristensen, Vessela N.; Gjerstad, Johannes & Nilsen, Hilde Loge [Show all 7 contributors for this article] (2019). Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. ISSN 0889-1591. 76, p. 82–96. doi: 10.1016/j.bbi.2018.11.008. Full text in Research Archive Show summary

  Background Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. Methods We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients). Results A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score. Conclusion We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

• Fang, Evandro Fei; Hou, Yujun; Palikaras, Konstantinos; Adriaanse, Bryan A.; Kerr, Jesse S. & Yang, Beimeng [Show all 20 contributors for this article] (2019). Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nature Neuroscience. ISSN 1097-6256. 22(3), p. 401–412. doi: 10.1038/s41593-018-0332-9. Full text in Research Archive Show summary

  Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer’s disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson’s disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ1–42 and Aβ1–40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.

• Kroustallaki, Pinelopi; Lirussi, Lisa; Huroz, Sergio Carracedo; You, Panpan; Esbensen, Qin Ying & Götz, Alexandra [Show all 11 contributors for this article] (2019). SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing. Cell reports. doi: 10.1016/j.celrep.2019.07.040. Full text in Research Archive Show summary

  Telomerase biogenesis is a complex process where several steps remain poorly understood. Single-strand-selective uracil-DNA glycosylase (SMUG1) associates with the DKC1-containing H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. Herein, we show that SMUG1 interacts with the telomeric RNA component (hTERC) and is required for co-transcriptional processing of the nascent transcript into mature hTERC. We demonstrate that SMUG1 regulates the presence of base modifications in hTERC, in a region between the CR4/CR5 domain and the H box. Increased levels of hTERC base modifications are accompanied by reduced DKC1 binding. Loss of SMUG1 leads to an imbalance between mature hTERC and its processing intermediates, leading to the accumulation of 3′-polyadenylated and 3′-extended intermediates that are degraded in an EXOSC10-independent RNA degradation pathway. Consequently, SMUG1-deprived cells exhibit telomerase deficiency, leading to impaired bone marrow proliferation in Smug1-knockout mice.

• Lautrup, Sofie Hindkjær; Lou, Guofeng; Aman, Yahyah; Nilsen, Hilde; Tao, Jun & Fang, Evandro Fei (2019). Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease. Neurochemistry International. ISSN 0197-0186. 129. doi: 10.1016/j.neuint.2019.104469. Full text in Research Archive
• Fang, Fei; Hou, Y; Palikaras, Konstantinos; Adriaanse, BA; Kerr, SJ & Yang, B [Show all 19 contributors for this article] (2019). Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nature Neuroscience. ISSN 1097-6256. 22(3), p. 401–412. doi: 10.1038/s41593-018-0332-9. Full text in Research Archive
• Lirussi, Lisa & Nilsen, Hilde (2019). Telomere maintenance: regulating hTERC fate through RNA modifications. Molecular and Cellular Oncology (MCO). 6:1670489(6), p. 1–3. doi: 10.1080/23723556.2019.1670489. Full text in Research Archive Show summary

  Disturbances in telomere maintenance are common in cancer. We recently showed that Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) promotes telomere homeostasis by regulating the stability of the telomeric RNA component (hTERC). SMUG1-mediated recognition of base modifications may function in a regulated process serving to fine-tune the levels of hTERC.

• Malt, Eva Albertsen; Juhasz, Katalin; Frengen, Anna Brzozowska; Wangensteen, Urd Teresia; Emilsen, Nina Merete & Hansen, Børre [Show all 8 contributors for this article] (2019). Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series. Molecular Genetics & Genomic Medicine. ISSN 2324-9269. 7(9). doi: 10.1002/mgg3.889. Full text in Research Archive Show summary

  Background: Genetic risk variants in the hemizygous allele may influence neuropsychiatric manifestations and clinical course in 3q29 deletion carriers. Methods: In‐depth phenotypic assessment in two deletion carriers included medical records, medical, genetic, psychiatric and neuropsychological evaluations, brain MRI scan and EEG. Blood samples were analyzed for copy number variations, and deep sequencing of the affected 3q29 region was performed in patients and seven first‐degree relatives. Risk variants were identified through bioinformatic analysis. Results: One deletion carrier was diagnosed with learning difficulties and childhood autism, the other with mild intellectual disability and schizophrenia. EEG abnormalities in childhood normalized in adulthood in both. Cognitive abilities improved during adolescence in one deletion carrier. Both had microcytic, hypochromic erythrocytes and suffered from chronic pain and fatigue. Molecular and bioinformatic analyses identified risk variants in the hemizygous allele that were not present in the homozygous state in relatives in genes involved in cilia function and insulin action in the autistic individual and in synaptic function and neurosteroid transport in the subject with schizophrenia. Conclusion: 3q29 deletion carriers may undergo developmental phenotypic transition and need regular medical follow‐up. Identified risk variants in the remaining hemizygous allele should be explored further in autism and schizophrenia research.

• Fang, Fei; Nilsen, Hilde; Storm-Mathisen, Jon & Bergersen, Linda Hildegard (2019). NO-age in Norway. Translational Medicine of Aging. 3, p. 37–39. doi: 10.1016/j.tma.2019.04.001. Full text in Research Archive
• Fang, Evandro Fei; Hou, Yujun; Lautrup, Sofie Hindkjær; Jensen, Martin Borch; Yang, Beimeng & Sengupta, Tanima [Show all 29 contributors for this article] (2019). NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nature Communications. 10:5284, p. 1–18. doi: 10.1038/s41467-019-13172-8. Full text in Research Archive Show summary

  Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

• Zheleva, Angelina; Gómez-Orte, Eva; Sáenz-Narciso, Beatriz; Ezcurra, Begoña; Kassahun, Henok & Toro, María de [Show all 10 contributors for this article] (2019). Reduction of mRNA export unmasks different tissue sensitivities to low mRNA levels during Caenorhabditis elegans development. PLoS Genetics. ISSN 1553-7390. 15:e1008338(9), p. 1–33. doi: 10.1371/journal.pgen.1008338. Full text in Research Archive Show summary

  Animal development requires the execution of specific transcriptional programs in different sets of cells to build tissues and functional organs. Transcripts are exported from the nucleus to the cytoplasm where they are translated into proteins that, ultimately, carry out the cellular functions. Here we show that in Caenorhabditis elegans, reduction of mRNA export strongly affects epithelial morphogenesis and germline proliferation while other tissues remain relatively unaffected. Epithelialization and gamete formation demand a large number of transcripts in the cytoplasm for the duration of these processes. In addition, our findings highlight the existence of a regulatory feedback mechanism that activates gene expression in response to low levels of cytoplasmic mRNA. We expand the genetic characterization of nuclear export factor NXF-1 to other members of the mRNA export pathway to model mRNA export and recycling of NXF-1 back to the nucleus. Our model explains how mutations in genes involved in general processes, such as mRNA export, may result in tissue-specific developmental phenotypes.

• Serebrenik, Artur A.; Starrett, Gabriel J.; Leenen, Sterre; Jarvis, Matthew C.; Shaban, Nadine M. & Salamango, Daniel J. [Show all 9 contributors for this article] (2019). The deaminase APOBEC3B triggers the death of cells lacking uracil DNA glycosylase. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 116(44), p. 22158–22163. doi: 10.1073/pnas.1904024116. Full text in Research Archive
• Arczewska, Katarzyna D.; Stachurska, Anna; Wojewódzka, Maria; Karpińska, Kamila; Kruszewski, Marcin & Nilsen, Hilde Loge [Show all 7 contributors for this article] (2018). hMTH1 is required for maintaining migration and invasion potential of human thyroid cancer cells. DNA Repair. ISSN 1568-7864. 69, p. 53–62. doi: 10.1016/j.dnarep.2018.07.006. Full text in Research Archive
• Torgovnick, Alessandro; Schiavi, Alfonso; Shaik, Anjumara; Kassahun, Henok; Maglioni, Silvia & Rea, Shane L [Show all 12 contributors for this article] (2018). BRCA1 and BARD1 mediate apoptotic resistance but not longevity upon mitochondrial stress in Caenorhabditis elegans. EMBO Reports. ISSN 1469-221X. 19(12). doi: 10.15252/embr.201845856. Full text in Research Archive
• Kassahun, Henok; Sengupta, Tanima; Schiavi, Alfonso; Maglioni, Silvia; Skjeldam, Hanne Kim & Arczewska, Katarzyna [Show all 11 contributors for this article] (2018). Constitutive MAP-kinase activation suppresses germline apoptosis in NTH-1 DNA glycosylase deficient C. elegans. DNA Repair. ISSN 1568-7864. 61, p. 46–55. doi: 10.1016/j.dnarep.2017.11.009. Full text in Research Archive Show summary

  Oxidation of DNA bases, an inevitable consequence of oxidative stress, requires the base excision repair (BER) pathway for repair. Caenorhabditis elegans is a well-established model to study phenotypic consequences and cellular responses to oxidative stress. To better understand how BER affects phenotypes associated with oxidative stress, we characterised the C. elegans nth-1 mutant, which lack the only DNA glycosylase dedicated to repair of oxidative DNA base damage, the NTH-1 DNA glycosylase. We show that nth-1 mutants have mitochondrial dysfunction characterised by lower mitochondrial DNA copy number, reduced mitochondrial membrane potential, and increased steady-state levels of reactive oxygen species. Consistently, nth-1 mutants express markers of chronic oxidative stress with high basal phosphorylation of MAP-kinases (MAPK) but further activation of MAPK in response to the superoxide generator paraquat is attenuated. Surprisingly, nth-1 mutants also failed to induce apoptosis in response to paraquat. The ability to induce apoptosis in response to paraquat was regained when basal MAPK activation was restored to wild type levels. In conclusion, the failure of nth-1 mutants to induce apoptosis in response to paraquat is not a direct effect of the DNA repair deficiency but an indirect consequence of the compensatory cellular stress response that includes MAPK activation.

• Fang, Evandro Fei; Waltz, Tyler B.; Kassahun, Henok; Lu, Qiping; Kerr, Jesse S. & Morevati, Marya [Show all 20 contributors for this article] (2017). Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Scientific Reports. 7. doi: 10.1038/srep46208. Full text in Research Archive Show summary

  Aging is a major international concern that brings formidable socioeconomic and healthcare challenges. Small molecules capable of improving the health of older individuals are being explored. Small molecules that enhance cellular stress resistance are a promising avenue to alleviate declines seen in human aging. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in C. elegans, an animal model of aging which shares many major longevity pathways with mammals. Tomatidine improves many C. elegans behaviors related to healthspan and muscle health, including increased pharyngeal pumping, swimming movement, and reduced percentage of severely damaged muscle cells. Microarray, imaging, and behavioral analyses reveal that tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy. This mechanism occurs in C. elegans, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions for diseases of aging.

• Fivenson, Elayne M.; Lautrup, Sofie; Sun, Nuo; Scheibye-Knudsen, Morten; Stevnsner, Tinna & Nilsen, Hilde Loge [Show all 8 contributors for this article] (2017). Mitophagy in neurodegeneration and aging. Neurochemistry International. ISSN 0197-0186. 109, p. 202–209. doi: 10.1016/j.neuint.2017.02.007. Full text in Research Archive Show summary

  Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ precursors and urolithins.

• Rolseth, Veslemøy; Gomez, Luisa Fernanda Luna; Olsen, Ann-Karin; Suganthan, Rajikala; Scheffler, Katja & Neurauter, Christine Gran [Show all 15 contributors for this article] (2017). No cancer predisposition or increased spontaneous mutation frequencies in NEIL DNA glycosylases-deficient mice. Scientific Reports. 7. doi: 10.1038/s41598-017-04472-4. Full text in Research Archive Show summary

  Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention. DNA glycosylases recognize and remove specific lesions in the first step of BER. The existence of a number of these enzymes with overlapping substrate specificities has been thought to be the reason why single knock-out models of individual DNA glycosylases are not cancer prone. In this work we have characterized DNA glycosylases NEIL1 and NEIL2 (Neil1−/−/Neil2−/−) double and NEIL1, NEIL2 and NEIL3 (Neil1−/−/Neil2−/−/Neil3−/−) triple knock-out mouse models. Unexpectedly, our results show that these mice are not prone to cancer and have no elevated mutation frequencies under normal physiological conditions. Moreover, telomere length is not affected and there was no accumulation of oxidative DNA damage compared to wild-type mice. These results strengthen the hypothesis that the NEIL enzymes are not simply back-up enzymes for each other but enzymes that have distinct functions beyond canonical repair.

• Nguyen, Chinh Bkrong Thi Thuy; Alsøe, Lene; Lindvall, Jessica Margareta; Sulheim, Dag; Fagermoen, Frode Even & Winger, Anette [Show all 9 contributors for this article] (2017). Whole blood gene expression in adolescent chronic fatigue syndrome: An exploratory cross-sectional study suggesting altered B cell differentiation and survival. Journal of Translational Medicine. 15. doi: 10.1186/s12967-017-1201-0. Full text in Research Archive Show summary

  Background Chronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group. Methods CFS patients (12–18 years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. Results A total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated. Conclusion Adolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise.

• Fang, Evandro Fei; Palikaras, Konstantinos; Sun, Nuo; Fivenson, Elayne M.; Spangler, Ryan D. & Kerr, Jesse S. [Show all 14 contributors for this article] (2017). In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice. Journal of Visualized Experiments. 2017(129). doi: 10.3791/56301. Full text in Research Archive

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• Komissarov, Artem; Wågbø, Ane Marit; Combes, Francis; Klinkenberg, Geir; Montaldo, Nicola Pietro & Nilsen, Hilde [Show all 7 contributors for this article] (2025). NTHL1 targeting modulates oxidative stress responses. Full text in Research Archive Show summary

  Base excision repair is the only DNA repair pathway active in both nuclei and mitochondria and is considered the major DNA repair pathway in neurons. The base excision repair enzyme Endonuclease III-like protein 1 (NTHL1) is a bifunctional glycosylase that mainly excises oxidized pyrimidines from DNA. In Caenorhabditis elegans, genetic perturbation of the NTHL1 orthologue leads to a mitohormetic response that protects dopaminergic neurons from oxidative stress (SenGupta et al., 2021). Similarly, in human cells, genetic NTHL1-perturbation prevents accumulation of toxic DNA repair intermediates and improves mitochondrial function (Hubers et al., 2024). Here, we hypothesize that pharmacologic NTHL1 perturbation could confer similar resistance against oxidative stress, and here we target NTHL1 using two different potential therapeutic modalities: Antisense oligonucleotides (ASOs) are short, synthetic single-stranded nucleic acids that bind complementary RNA to modulate gene expression and can be delivered directly to the central nervous system with excellent selectivity and pharmacokinetic stability over several months (Crooke et al 2021). Small molecule inhibitors are low–molecular-weight organic compounds that bind specific sites on biological targets to block their activity.

• Kleve, Guro; Santa, Chiara Dalla; Kristiansen, Felicia Iselin Svensson; Tegnander, Marita; Buch, Victoria & Hagemann, Cecilie Steen [Show all 29 contributors for this article] (2025). Digital home-based multimodal prehabilitation of colorectal cancer patients prior to surgery (the dHOPE study): a non-inferiority clinical trial protocol. doi: 10.3389/fdgth.2025.1609678. Full text in Research Archive Show summary

  Cancer surgery is associated with risk of complications and loss of function. Vulnerability factors, such as advanced age, malnutrition, smoking, comorbidity, frailty, and low socioeconomic status increase the risk. Lifestyle intervention prior to surgery, known as prehabilitation, often include physical activity, nutritional support, psychological coaching, and smoking cessation, increase functional reserves and reduce postoperative complications. Most importantly, it prevents loss of functional capacity and dependence. Methods The dHOPE study is a three-armed, open-labelled, parallel-group randomized controlled trial (RCT) with non-inferiority design to compare a digital home-based prehabilitation program with a hospital-based program or no organized prehabilitation. In addition, the dHOPE study aims to identify measurable parameters reflecting the effect of prehabilitation, thus preparing for future personalization of the prehabilitation programs. Discussion The feasibility of multimodal prehabilitation is threatened by low compliance to hospital-based programs due to burdensome commuting, even in central and metropolitan areas. In sparsely populated countries, this challenge is even more pronounced. To ensure equal healthcare to all citizens regardless of address or economic situation, there is a need to transfer the prehabilitation program to the patients’ homes. Thus, the primary hypothesis of dHOPE is that a digital home-based program is not inferior to a hospital-based program. Moreover, given the patient diversity, prehabilitation must be personalized to meet individual profiles or needs. An exploratory subtask of dHOPE is to confirm the utility of clinical, genetic, and molecular factors in evaluating prehabilitation response ultimately to identify new biomarkers and develop medical software for individual risk stratification and development of personalized prehabilitation programs. Clinical Trial registration https://clinicaltrials.gov/ , identifier (NCT06231576).

• Nilsen, Hilde (2025). NAD augmentation for Ataxia Telangiectasia. Full text in Research Archive
• Nilsen, Hilde (2025). Gene Therapy for A-T Workshop. Full text in Research Archive Show summary

  Discussion meeting on clinical pilepine for therapy in A-T

• Nilsen, Hilde (2025). NRK Radio EKKO. [Radio]. NRK P2. Full text in Research Archive
• Haarberg, Odin Weberg; Holland, Petter & Nilsen, Hilde (2025). Kan aldringsbiologien gi oss en ny tilnærming til helse og sykdom? 22(3), p. 219–237. doi: 10.5617/michael.12617. Full text in Research Archive Show summary

  Aldring og helse får stadig mer oppmerksomhet. Medier, ikke minst sosiale medier, flommer over av artikler om biohacking (overstyring av biologiske prosesser). Talspersoner for biohacking ser for seg kroppen som en kompleks maskin der de individuelle delene kan erstattes, og kjemien som foregår i cellene som bygger opp denne maskinen, kan optimaliseres ved å overstyre biologiske prosesser for å unngå aldring. Lite av det som foreslås er fundert i solid kunnskap om effekt, men i likhet med mange gode historier har flere av ideene et snev av sannhet i seg. I denne kronikken gir vi en oversikt over mekanismene som fører til aldring. Vi vil også diskutere hvordan disse kan være relevante for forståelsen av sykdom og for hvordan vi kan få flest mulig sunne leveår.

• Suaste, Veronica; Daza-Torres, Maria L.; Montesino-Lopez, José Cricelio & Nilsen, Hilde (2024). Is age predictable from PBMCs transcriptome? Insights from Bayesian models. Full text in Research Archive
• Wang, Heling; Siow, Richard; Schmauck-Medina, Tomás Alejandro; Zhang, Jianying; Sandset, Per Morten & Filshie, Clare [Show all 38 contributors for this article] (2024). Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies. The journals of gerontology. Series A, Biological sciences and medical sciences. ISSN 1079-5006. 79(4), p. 1–10. doi: 10.1093/gerona/glae029. Full text in Research Archive Show summary

  Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

• SenGupta, Tanima; Nilsen, Hilde Loge & Rundén-Pran, Elise (2024). The Role of DNA repair in aging and neurodegeneration. Full text in Research Archive
• Prebensen, Christian Haugland; Lefol, Yohan Pierre; Myhre, Peder Langeland; Lüders, Torben; Jonassen, Christine M & Blomfeldt, Anita [Show all 9 contributors for this article] (2023). Author Correction: Longitudinal whole blood transcriptomic analysis characterizes neutrophil activation and interferon signaling in moderate and severe COVID-19 (Scientific Reports, (2023), 13, 1, (10368), 10.1038/s41598-023-37606-y). Scientific Reports. 13(1). doi: 10.1038/s41598-023-39872-2. Full text in Research Archive
• Vinje, Victoria; Cao, Shu-qin; Heck, Siri Lagethon; Wisløff, Torbjørn; Klæboe, Lars Gunnar & Nilsen, Hilde Loge [Show all 9 contributors for this article] (2023). Rationale And Design Of The NARNIA Trial: The Effect Of NicotinAmide Riboside ON Myocardial And Skeletal Muscle Injury And Function In Patients With Metastatic Breast Cancer Receiving Anthracyclines. Full text in Research Archive
• Suaste, Veronica & Nilsen, Hilde (2022). Characterization of DNA damage response ageing signatures. Full text in Research Archive
• Tasken, Kjetil; Russnes, Hege Elisabeth Giercksky; Aas, Eline; Bjørge, Line; Blix, Egil Støre & Ahlquist, Terje C. [Show all 116 contributors for this article] (2022). A national precision cancer medicine implementation initiative for Norway. Nature Medicine. ISSN 1078-8956. 28(5), p. 885–887. doi: 10.1038/s41591-022-01777-4. Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Correction to: Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway (Journal of Translational Medicine, (2022), 20, 1, (225), 10.1186/s12967-022-03432-5). Journal of Translational Medicine. 20(1). doi: 10.1186/s12967-022-03518-0. Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway. Journal of Translational Medicine. 20(1), p. 1–11. doi: 10.1186/s12967-022-03432-5. Full text in Research Archive Show summary

  Background Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. Methods In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient’s tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system.

• Palikaras, Konstantinos; Sengupta, Tanima; Nilsen, Hilde & Tavernarakis, Nektarios (2022). Assessment of dopaminergic neuron degeneration in a C. elegans model of Parkinson's disease. STAR Protocols. 3(2). doi: 10.1016/j.xpro.2022.101264. Full text in Research Archive
• Einevoll, Gaute & Nilsen, Hilde (2021). Podcast #43: Om å stoppe aldring. [Internet]. Podcast: Vett og vitenskap med Gaute Einevoll. Full text in Research Archive
• Safavi, Shiva; Larouche, Ariane; Zahn, Astrid; Patenaude, Anne-Marie; Domanska, Diana & Dionne, Kiersten [Show all 17 contributors for this article] (2021). Erratum: The uracil-DNA glycosylase UNG protects the fitness of normal and cancer B cells expressing AID (NAR Cancer (2020) 2:3 (zcaa019) DOI: 10.1093/narcan/zcaa019). NAR Cancer. 3(1). doi: 10.1093/NARCAN/ZCAA045. Full text in Research Archive
• Bos, Steffan Daniel; Brorson, Ina Skaara; Eriksson, Anna; Leikfoss, Ingvild Sørum; Vitelli, Valeria & Celius, Elisabeth Gulowsen [Show all 10 contributors for this article] (2019). Differential gene expression analysis of CD8+ T cells from multiple sclerosis patients and healthy controls. Full text in Research Archive
• Gudmundsrud, Ruben; Lautrup, Sofie; Nilsen, Hilde Loge; Bohr, Vilhelm & Fang, Fei (2018). Mitofagi i nevrodegenerasjon og aldring. BestPractice Norge. 109, p. 202–209. doi: 10.1016/j.neuint.2017.02.007. Full text in Research Archive
• Alsøe, Lene; Wennerström, Anna Berit; Liu, Yan; Esbensen, Qin Ying; Bjørset, Randi & Penz, Christine [Show all 10 contributors for this article] (2018). Do APOBEC proteins contribute to genomic instability in colitis-associated colorectal cancer? Full text in Research Archive
• Høyer, Helle; Tveten, Kristian; Røsby, Oddveig; Hilmarsen, Hilde T; Busk, Øyvind & Svendsen, Marit [Show all 12 contributors for this article] (2018). A novel AARS variant identified in three CMT2 families. Full text in Research Archive
• Eddershaw, Alice; Dalhus, Bjørn; Gileadi, Opher; Gräslund, Susanne; Güneş, İrşil & Helleday, Thomas [Show all 25 contributors for this article] (2026). A high-throughput screening dataset of small-molecule inhibitors across human DNA glycosylases. Social Science Research Network. doi: 10.2139/ssrn.7524643. Full text in Research Archive Show summary

  The base excision repair pathway removes small base lesions from DNA and is initiated in humans by one of eleven DNA glycosylases with overlapping substrate specificities. Despite their central role in genome maintenance and transcription, systematic datasets describing small-molecule binders or inhibitors of DNA glycosylases are lacking. Here, through a collaborative effort across Scandinavia, we establish a high-throughput biochemical assay platform for human DNA glycosylases and use it to generate a systematic small-molecule screening dataset. A chemogenomic library was screened against nine glycosylases with assays of sufficient quality for hit identification, yielding primary screening and concentration-response data and identifying multiple previously unreported inhibitors. All primary and processed data, along with detailed assay protocols and metadata, are publicly available to support reuse in chemical biology, further compound optimization, assay development and comparative studies of DNA repair enzymes.

• Zhu, Hengyi; Brede, Dag Anders; Eide, Dag Markus; Maremonti, Erica; Nilsen, Hilde & Lind, Ole Christian (2026). Mechanistic investigation of chronic ionizing radiation-induced reprotoxic effects in model organism Caenorhabditis elegans. Norges miljø- og biovitenskapelige universitet (NMBU). ISSN 9788257523442. Full text in Research Archive Show summary

  Ionizing radiation is ubiquitous in the environment both due to natural occurring and artificial radioactive sources. They emit primarily alpha (α), beta (β) particles, and gamma (γ) photons, resulting in chronic exposure to ionizing radiation for all organisms. For humans, inhalation of radon (222Rn) and thoron (220Rn) and their decay products contribute a substantial 60% of the annual effective dose from natural sources and is dominated by α particle radiation, with additional β and γ components. Chronic exposure to ionizing radiation can cause dose-dependent increases in DNA damage, germ cell apoptosis, and reproductive defects, potentially threaten long-term organismal fitness and, ultimately, ecosystem sustainability. In the nematode Caenorhabditis elegans (C. elegans), one of the most radioresistant metazoans, recent work has shown that chronic γ irradiation at 40 mGy/h (70 h; total dose 2.8 Gy) induces reprotoxic effects in directly irradiated generation primarily by disrupting spermatogenesis. In parentally irradiated F1 generation, embryos can still develop into fertile adults despite carrying substantial levels of DNA damage. In contrast, the reprotoxic effects of chronic α exposure in animals have not been subject to detailed mechanistic investigations. In this thesis, we aimed to elucidate the molecular and cellular processes underlying γ irradiation induced impairment of spermatogenesis in the directly irradiated generation (Paper I), to identify mechanisms that enable the maintenance of fertility in the generation born to irradiated parents (Paper II), and to characterize uptake and dose-dependent adverse effects of chronic 224Ra exposure (Paper III). To address these aims, C. elegans populations were chronically exposed to γ rays from a Cobolt-60 (60Co) source at dose rates ranging from 1 to 100 mGy/h (Paper I & II), or radium-224 dichloride (224RaCl2) solutions at initial α activity concentrations ranging from 0 to 2107 Bq/mL (Paper III). Specifically, exposure to 224Ra was performed in closed-vial system to ensure both 224Ra and its short-lived decay products including 220Rn contribute to the exposure. Following the exposures, phenotypic investigations relevant to reproduction and transcriptomic analysis at the population level were conducted. As important tools for functional investigation, RNA interference (RNAi) gene knockdown and deletion mutants were used to dissect the roles of DNA double strand breaks (DSB) repair pathways including homologous recombination repair (HRR; rad-51, mre-11, spo-11), polymerase theta-mediated end joining (TMEJ; polq-1), and non-homologous end joining (NHEJ; lig-4) in alleviating damage induced by chronic ionizing radiation exposure (Paper I & Paper II).

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