Nicola Pietro Montaldo

• 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.

• 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.

• 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.

• 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.

• 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
• 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.

• 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.

• Glærum, Ingvild Lynneberg; Dunville, Keagan; Moan, Kristian Magnus; Krause, Maike; Montaldo, Nicola Pietro & Kirikae, Hinaco [Show all 10 contributors for this article] (2024). Postnatal persistence of hippocampal Cajal-Retzius cells has a critical role in the establishment of the hippocampal circuit. Development. ISSN 0950-1991. 151(1). doi: 10.1242/dev.202236. Full text in Research Archive
• Bordin, Diana Lilian; Grooms, Kayla Mae; Montaldo, Nicola Pietro; Martin, Sarah Louise Fordyce; Sætrom, Pål & Samson, Leona D. [Show all 8 contributors for this article] (2024). Loss of alkyladenine DNA glycosylase alters gene expression in the developing mouse brain and leads to reduced anxiety and improved memory. DNA Repair. ISSN 1568-7864. 135, p. 1–10. doi: 10.1016/j.dnarep.2024.103632. Full text in Research Archive Show summary

  Neurodevelopment is a tightly coordinated process, during which the genome is exposed to spectra of endogenous agents at different stages of differentiation. Emerging evidence indicates that DNA damage is an important feature of developing brain, tightly linked to gene expression and neuronal activity. Some of the most frequent DNA damage includes changes to DNA bases, which are recognized by DNA glycosylases and repaired through base excision repair (BER) pathway. The only mammalian DNA glycosylase able to remove frequent alkylated DNA based is alkyladenine DNA glycosylase (Aag, aka Mpg). We recently demonstrated that, besides its role in DNA repair, AAG affects expression of neurodevelopmental genes in human cells. Aag was further proposed to act as reader of epigenetic marks, including 5-hydroxymethylcytosine (5hmC), in the mouse brain. Despite the potential Aag involvement in the key brain processes, the impact of Aag loss on developing brain remains unknown. Here, by using Aag knockout (Aag-/-) mice, we show that Aag absence leads to reduced DNA break levels, evident in lowered number of γH2AX foci in postnatal day 5 (P5) hippocampi. This is accompanied by changes in 5hmC signal intensity in different hippocampal regions. Transcriptome analysis of hippocampi and prefrontal cortex, at different developmental stages, indicates that lack of Aag alters gene expression, primarily of genes involved in regulation of response to stress. Across all developmental stages tested aldehyde dehydrogenase 2 (Aldh2) emerged as one of the most prominent genes deregulated in Aag-dependent manner. In line with the changes in hippocampal DNA damage levels and the gene expression, adult Aag-/- mice exhibit altered behavior, evident in decreased anxiety levels determined in the Elevated Zero Maze and increased alternations in the Elevated T Maze tests. Taken together these results suggests that Aag has functions in modulation of genome dynamics during brain development, important for animal behavior.

• Loevenich, Simon; Montaldo, Nicola Pietro; Wickenhagen, Arthur; Sherstova, Tatyana; Loon, Barbara van & Boyartchuk, Victor [Show all 7 contributors for this article] (2023). Human metapneumovirus driven IFN-β production antagonizes macrophage transcriptional induction of IL1-β in response to bacterial pathogens. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1173605. Full text in Research Archive Show summary

  Human metapneumovirus (HMPV) is a pneumovirus that may cause severe respiratory disease in humans. HMPV infection has been found to increase susceptibility to bacterial superinfections leading to increased morbidity and mortality. The molecular mechanisms underlying HMPV-mediated increase in bacterial susceptibility are poorly understood and largely understudied. Type I interferons (IFNs), while critical for antiviral defenses, may often have detrimental effects by skewing the host immune response and cytokine output of immune cells. It is currently unknown if HMPV skews the inflammatory response in human macrophages triggered by bacterial stimuli. Here we report that HMPV pre-infection impacts production of specific cytokines. HMPV strongly suppresses IL-1β transcription in response to LPS or heat-killed Pseudomonas aeruginosa and Streptococcus pneumonia , while enhancing mRNA levels of IL-6, TNF-α and IFN-β. We demonstrate that in human macrophages the HMPV-mediated suppression of IL-1β transcription requires TANK-binding kinase 1 (TBK1) and signaling via the IFN-β-IFNAR axis. Interestingly, our results show that HMPV pre-infection did not impair the LPS-stimulated activation of NF-κB and HIF-1α, transcription factors that stimulate IL-1β mRNA synthesis in human cells. Furthermore, we determined that sequential HMPV-LPS treatment resulted in accumulation of the repressive epigenetic mark H3K27me3 at the IL1B promoter. Thus, for the first time we present data revealing the molecular mechanisms by which HMPV shapes the cytokine output of human macrophages exposed to bacterial pathogens/LPS, which appears to be dependent on epigenetic reprogramming at the IL1B promoter leading to reduced synthesis of IL-1β. These results may improve current understanding of the role of type I IFNs in respiratory disease mediated not only by HMPV, but also by other respiratory viruses that are associated with superinfections.

• 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.

• 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.

• Aprigliano, Rossana; Aksu, Merdane Ezgi; Bradamante, Stefano; Mihaljevic, Boris; Wang, Wei & Rian, Kristin [Show all 19 contributors for this article] (2021). Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities. Cell Reports Medicine. 2(4). doi: 10.1016/j.xcrm.2021.100240. Full text in Research Archive Show summary

  Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.

• Rolinski, Milosz; Montaldo, Nicola Pietro; Aksu, Merdane Ezgi; Martin, Sarah Fordyce; Brambilla, Alessandro & Kunath, Nicolas [Show all 13 contributors for this article] (2021). Loss of Mediator complex subunit 13 (MED13) promotes resistance to alkylation through cyclin D1 upregulation. Nucleic Acids Research (NAR). ISSN 0305-1048. 49(3), p. 1470–1484. doi: 10.1093/nar/gkaa1289. Full text in Research Archive Show summary

  Alkylating drugs are among the most often used chemotherapeutics. While cancer cells frequently develop resistance to alkylation treatments, detailed understanding of mechanisms that lead to the resistance is limited. Here, by using genome-wide CRISPR–Cas9 based screen, we identify transcriptional Mediator complex subunit 13 (MED13) as a novel modulator of alkylation response. The alkylation exposure causes significant MED13 downregulation, while complete loss of MED13 results in reduced apoptosis and resistance to alkylating agents. Transcriptome analysis identified cyclin D1 (CCND1) as one of the highly overexpressed genes in MED13 knock-out (KO) cells, characterized by shorter G1 phase. MED13 is able to bind to CCND1 regulatory elements thus influencing the expression. The resistance of MED13 KO cells is directly dependent on the cyclin D1 overexpression, and its downregulation is sufficient to re-sensitize the cells to alkylating agents. We further demonstrate the therapeutic potential of MED13-mediated response, by applying combinatory treatment with CDK8/19 inhibitor Senexin A. Importantly, the treatment with Senexin A stabilizes MED13, and in combination with alkylating agents significantly reduces viability of cancer cells. In summary, our findings identify novel alkylation stress response mechanism dependent on MED13 and cyclin D1 that can serve as basis for development of innovative therapeutic strategies.

• Montaldo, Nicola Pietro; Bordin, Diana Lilian; Brambilla, Alessandro; Rösinger, Marcel; Martin, Sarah Fordyce & Bjørås, Karine Øian [Show all 16 contributors for this article] (2019). Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression. Nature Communications. 10(1). doi: 10.1038/s41467-019-13394-w. Full text in Research Archive Show summary

  Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression.

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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.

• Anthonsen, Marit Walbye; Boyartchuk, Victor; Loevenich, Simon; Loon, Barbara van; Montaldo, Nicola Pietro & Sherstova, Tatyana (2019). Human metapneumovirus impairs antibacterial transcription by introducing H3K27 trimethylation at the IL1B promoter. 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.

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