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

Author

Listed:
  • Jip Verschuren

    (Leiden University Medical Center)

  • Robin Schendel

    (Leiden University Medical Center)

  • Ivo Bostelen

    (Leiden University Medical Center)

  • Alex E. E. Verkennis

    (Hubrecht Institute–KNAW and University Medical Center Utrecht)

  • Puck Knipscheer

    (Leiden University Medical Center
    Hubrecht Institute–KNAW and University Medical Center Utrecht)

  • Marcel Tijsterman

    (Leiden University Medical Center
    Leiden University)

Abstract

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.

Suggested Citation

  • Jip Verschuren & Robin Schendel & Ivo Bostelen & Alex E. E. Verkennis & Puck Knipscheer & Marcel Tijsterman, 2025. "FAN1-mediated translesion synthesis and POLQ/HELQ-mediated end joining generate interstrand crosslink-induced mutations," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57764-z
    DOI: 10.1038/s41467-025-57764-z
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    References listed on IDEAS

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    1. R. Alex Wu & Daniel R. Semlow & Ashley N. Kamimae-Lanning & Olga V. Kochenova & Gheorghe Chistol & Michael R. Hodskinson & Ravindra Amunugama & Justin L. Sparks & Meng Wang & Lin Deng & Claudia A. Mim, 2019. "TRAIP is a master regulator of DNA interstrand crosslink repair," Nature, Nature, vol. 567(7747), pages 267-272, March.
    2. Nadezda V. Volkova & Bettina Meier & Víctor González-Huici & Simone Bertolini & Santiago Gonzalez & Harald Vöhringer & Federico Abascal & Iñigo Martincorena & Peter J. Campbell & Anton Gartner & Morit, 2020. "Mutational signatures are jointly shaped by DNA damage and repair," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
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