Reference - Detail
| RRC ID | 84213 |
|---|---|
| Author | Verschuren J, van Schendel R, van Bostelen I, Verkennis AEE, Knipscheer P, Tijsterman M. |
| Title | FAN1-mediated translesion synthesis and POLQ/HELQ-mediated end joining generate interstrand crosslink-induced mutations. |
| Journal | Nat Commun |
| 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. |
| Volume | 16(1) |
| Pages | 2495 |
| Published | 2025-3-13 |
| DOI | 10.1038/s41467-025-57764-z |
| PII | 10.1038/s41467-025-57764-z |
| PMID | 40082407 |
| PMC | PMC11906846 |
| MeSH | Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism DNA Damage DNA End-Joining Repair* DNA Helicases* / genetics DNA Helicases* / metabolism DNA Repair* DNA Replication DNA-Directed DNA Polymerase* / genetics DNA-Directed DNA Polymerase* / metabolism Exodeoxyribonucleases* / genetics Exodeoxyribonucleases* / metabolism Mutation* Polymorphism, Single Nucleotide Translesion DNA Synthesis |
| Resource | |
| C.elegans | tm1298 tm2026 tm2134 tm432 tm3081 |