FIRRM cooperates with FIGNL1 to promote RAD51 disassembly during DNA repair
Edgar Pinedo-Carpio, Julien Dessapt, Adèle Beneyton, Lauralicia Sacre, M.A. Bérubé, Romain Villot, Élise G. Lavoie, Yan Coulombe, Andréanne Blondeau, Jonathan Boulais, Abba Malina, Vincent Luo, Anna-Maria Lazaratos, Jean‐François Côté, Frédérick A. Mallette, Alba Guarné, Jean‐Yves Masson, Amélie Fradet‐Turcotte, Alexandre Orthwein
Abstract
Interstrand DNA cross-links (ICLs) represent complex lesions that compromise genomic stability. Several pathways have been involved in ICL repair, but the extent of factors involved in the resolution of ICL-induced DNA double-strand breaks (DSBs) remains poorly defined. Using CRISPR-based genomics, we identified FIGNL1 interacting regulator of recombination and mitosis (FIRRM) as a sensitizer of the ICL-inducing agent mafosfamide. Mechanistically, we showed that FIRRM, like its interactor Fidgetin like 1 (FIGNL1), contributes to the resolution of RAD51 foci at ICL-induced DSBs. While the stability of FIGNL1 and FIRRM is interdependent, expression of a mutant of FIRRM (∆WCF), which stabilizes the protein in the absence of FIGNL1, allows the resolution of RAD51 foci and cell survival, suggesting that FIRRM has FIGNL1-independent function during DNA repair. In line with this model, FIRRM binds preferentially single-stranded DNA in vitro, raising the possibility that it directly contributes to RAD51 disassembly by interacting with DNA. Together, our findings establish FIRRM as a promoting factor of ICL repair.