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<p>To counteract the damaging effects of DNA interstrand crosslinks (ICLs), cells have evolved various specialized ICL repair pathways. However, how ICL repair impacts genetic integrity remains incompletely understood. Here, we determined the mutagenic consequences of psoralen ICL repair in the animal model <i>C. elegans</i> and identify two mutagenic repair mechanisms: (i) translesion synthesis through POLH and REV1/3-mediated bypass, leading to single nucleotide polymorphisms (SNVs), and (ii) end joining via POLQ or HELQ action resulting in deletions. While we found no role for the Fanconi anemia genes FANCD2 and FANCI, disruption of TRAIP, which triggers unloading of the CMG helicase at sites of blocked replication, led to a strikingly altered repair profile, suggesting a role for DNA replication in the etiology of ICL-induced deletions. TRAIP deficiency did not affect SNV formation; instead, we found these SNVs to depend on the functionality of the Fanconi anemia-associated nuclease FAN1.</p>

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FAN1-mediated translesion synthesis and POLQ/HELQ-mediated end joining generate interstrand crosslink-induced mutations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月13日

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  • Jip Verschuren,
  • Robin van Schendel,
  • Ivo van Bostelen,
  • Alex E. E. Verkennis,
  • Puck Knipscheer,
  • Marcel Tijsterman

摘要

To counteract the damaging effects of DNA interstrand crosslinks (ICLs), cells have evolved various specialized ICL repair pathways. However, how ICL repair impacts genetic integrity remains incompletely understood. Here, we determined the mutagenic consequences of psoralen ICL repair in the animal model C. elegans and identify two mutagenic repair mechanisms: (i) translesion synthesis through POLH and REV1/3-mediated bypass, leading to single nucleotide polymorphisms (SNVs), and (ii) end joining via POLQ or HELQ action resulting in deletions. While we found no role for the Fanconi anemia genes FANCD2 and FANCI, disruption of TRAIP, which triggers unloading of the CMG helicase at sites of blocked replication, led to a strikingly altered repair profile, suggesting a role for DNA replication in the etiology of ICL-induced deletions. TRAIP deficiency did not affect SNV formation; instead, we found these SNVs to depend on the functionality of the Fanconi anemia-associated nuclease FAN1.