Alexander Myhr Skjetne

• Hubers, Lisa Anne; Skjetne, Alexander Myhr; Luna, Luisa; Lefol, Yohan Pierre; Lund, Solveig Osnes & Wågbø, Ane Marit [Vis alle 15 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• 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), s. 1–12. doi: 10.1093/narcan/zcaf050. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Hubers, Lisa Anne; Skjetne, Alexander Myhr; Luna, Luisa; Lefol, Yohan Pierre; Lund, Solveig Osnes & Wågbø, Ane Marit [Vis alle 14 forfattere av denne artikkelen] (2024). Functional Impact of Nth-like DNA glycosylase on Mitochondrial Dynamics. bioRxiv. ISSN 2692-8205. doi: 10.1101/2024.10.10.617535. Fulltekst i vitenarkiv Vis sammendrag

  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.

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