%0 Journal Article %T Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ %+ Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer %+ Genome dynamics in the immune system (Equipe Inserm U1163) %+ Immunobiologie de l'Infection - Immunobiology of Infection %+ IMIM-Hospital del Mar %A Yu, Wei %A Lescale, Chloé %A Babin, Loelia %A Bedora-Faure, Marie %A Lenden-Hasse, Hélène %A Baron, Ludivine %A Demangel, Caroline %A Yelamos, José %A Brunet, Erika %A Deriano, Ludovic %Z This project is funded by the Institut Pasteur (L.D. and C.D. labs), the Institut National du Cancer (INCa Grant # PLBIO16-181 to L.D. and E.B. labs), the Ligue Nationale Contre le Cancer (Équipe Labellisée 2019 L.D. lab and Équipe Labellisée 2017 and 2020 E.B. lab) the Cancéropôle IdF-INCa (Emergence 2016 grant to L.D. and C.D.), the Spanish Ministerio de Economía, Industria y Competitividad (Grant SAF2017-83565-R to J.Y.) as well as by the Fundación Científica de la Asociación Española Contra el Cáncer (AECC) (Grant PROYEI6018YÉLA to J.Y.). %< avec comité de lecture %@ 2041-1723 %J Nature Communications %I Nature Publishing Group %V 11 %N 1 %P 5239 %8 2020-10-16 %D 2020 %R 10.1038/s41467-020-19060-w %M 33067475 %Z Life Sciences [q-bio]/Human health and pathology/Infectious diseasesJournal articles %X The alternative non-homologous end-joining (NHEJ) pathway promotes DNA double-strand break (DSB) repair in cells deficient for NHEJ or homologous recombination, suggesting that it operates at all stages of the cell cycle. Here, we use an approach in which DNA breaks can be induced in G1 cells and their repair tracked, enabling us to show that joining of DSBs is not functional in G1-arrested XRCC4-deficient cells. Cell cycle entry into S-G2/M restores DSB repair by Pol θ-dependent and PARP1-independent alternative NHEJ with repair products bearing kilo-base long DNA end resection, micro-homologies and chromosome translocations. We identify a synthetic lethal interaction between XRCC4 and Pol θ under conditions of G1 DSBs, associated with accumulation of unresolved DNA ends in S-G2/M. Collectively, our results support the conclusion that the repair of G1 DSBs progressing to S-G2/M by alternative NHEJ drives genomic instability and represent an attractive target for future DNA repair-based cancer therapies. %G English %Z We thank the Institut Pasteur genomics and cytometry platforms for help with sequencing and cell sorting, Frederick Alt and members of his lab for tremendous help with LAM-HTGTS experiments, Barry Sleckman for providing the RAG2-Thy1.1 complementation vector, Joy Bianchi for providing the Rag2−/− p53−/− v-Abl pro-B cell lines, Carine Giovannangeli and Anne de Cian for providing the Cas9 protein and Thomas Mercher for helpful discussions and suggestions. %2 https://pasteur.hal.science/pasteur-03262335/document %2 https://pasteur.hal.science/pasteur-03262335/file/s41467-020-19060-w.pdf %L pasteur-03262335 %U https://pasteur.hal.science/pasteur-03262335 %~ INSERM %~ PASTEUR %~ ATP-IMMUN %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ UP-SANTE