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<p>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 &gt; 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 <i>N</i><sup><i>2</i></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.</p>

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Tissue-specific mutagenesis from endogenous guanine damage is suppressed by Polκ and DNA repair

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Yang Jiang,
  • Moritz Przybilla,
  • Linda Bakker,
  • Foster C. Jacobs,
  • Dylan Mckeon,
  • Roxanne van der Sluijs,
  • Koichi Sato,
  • Juliëtte Wezenbeek,
  • Joeri van Strien,
  • Jeroen Willems,
  • Alexander E. E. Verkennis,
  • Jamie Barnett,
  • Adrian Baez Ortega,
  • Federico Abascal,
  • Peter W. Villalta,
  • Puck Knipscheer,
  • Inigo Martincorena,
  • Silvia Balbo,
  • Juan Garaycoechea

摘要

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 N2-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.