Tissue-specific mutagenesis from endogenous guanine damage is suppressed by Polκ and DNA repair
Knowledge of mutational patterns has expanded significantly, but linking these patterns to specific molecular mechanisms or sources of endogenous DNA damage remains challenging. Translesion synthesis (TLS) is a key determinant of mutagenesis, yet the endogenous lesions that require TLS and how TLS polymerases shape mammalian mutational landscapes are unclear. Here, we characterize somatic mutational patterns across mouse tissues deficient in the TLS polymerase Polκ and find that Polκ suppresses a distinct tissue-specific mutational signature in the liver and kidney. This signature, enriched for C > A/G/T mutations with strong transcriptional-strand bias, indicates that Polκ performs error-free bypass of endogenous guanine adducts. Nucleotide excision repair (NER) acts in parallel, mitigating some of this damage. Targeted adductomics and biochemical analyses identify endogenous N<sup>2</sup>-dG lesions requiring Polκ-mediated bypass, while untargeted adductomics reveal new guanine lesions that engage NER. These findings uncover the nature of endogenous DNA damage and the coordinated roles of repair and tolerance pathways that limit mutagenesis in tissues.
Authors
- D.C. McKeon
- Yang Jiang (ORCID: https://orcid.org/0000-0002-9078-3453)
- Linda V. Bakker (ORCID: https://orcid.org/0009-0004-9308-393X)
- Koichi Sato (ORCID: https://orcid.org/0000-0002-0574-774X)
- Peter W. Villalta (ORCID: https://orcid.org/0000-0002-0067-3083)
- Iñigo Martincorena (ORCID: https://orcid.org/0000-0003-1122-4416)
- Federico Abascal (ORCID: https://orcid.org/0000-0002-6201-1587)
- Jamie Barnett (ORCID: https://orcid.org/0000-0003-0731-7249)
- Alexander E. E. Verkennis
- Juliëtte Wezenbeek
- Foster C. Jacobs
- Juan I. Garaycoechea (ORCID: https://orcid.org/0000-0001-5626-808X)
- Roxanne van der Sluijs (ORCID: https://orcid.org/0009-0005-2942-8144)
- Silvia Balbo (ORCID: https://orcid.org/0000-0002-7686-0504)
- Adrian Baez‐Ortega (ORCID: https://orcid.org/0000-0002-9201-4420)
- Moritz Jakob Przybilla (ORCID: https://orcid.org/0000-0001-5645-9492)
- Puck Knipscheer
- Joeri van Strien (ORCID: https://orcid.org/0000-0003-4285-4429)
- Jeroen Willems
Institutions
- Wellcome Sanger Institute (GB)
- University Medical Center Utrecht (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- University of Minnesota Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1038/s41467-025-67072-1
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81