Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ
| Autor: | Loelia Babin, Caroline Demangel, Hélène Lenden-Hasse, Ludovic Deriano, Ludivine Baron, Erika Brunet, José Yélamos, Marie Bedora-Faure, Wei Yu, Chloé Lescale |
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| Přispěvatelé: | Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris], Genome dynamics in the immune system (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie de l'Infection - Immunobiology of Infection, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), IMIM-Hospital del Mar, Generalitat de Catalunya, 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.)., 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., Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Demangel, Caroline, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris] |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genome instability DNA End-Joining Repair MESH: DNA Breaks Double-Stranded Poly (ADP-Ribose) Polymerase-1 General Physics and Astronomy MESH: Cell Cycle MESH: Poly (ADP-Ribose) Polymerase-1 Genome Càncer--Tractament chemistry.chemical_compound Mice 0302 clinical medicine [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases DNA Breaks Double-Stranded MESH: Animals lcsh:Science Double strand Multidisciplinary Cell Cycle DNA repair protein XRCC4 Cell cycle 3. Good health Cell biology DNA-Binding Proteins 030220 oncology & carcinogenesis [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases Cell division DNA repair ADN--Dany DNA recombination Science Double-strand DNA breaks MESH: G1 Phase General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Targeted therapies Animals MESH: Mice B cells fungi G1 Phase General Chemistry MESH: DNA End-Joining Repair enzymes and coenzymes (carbohydrates) 030104 developmental biology chemistry lcsh:Q Homologous recombination DNA MESH: DNA-Binding Proteins |
| Zdroj: | Nature Communications Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.5239. ⟨10.1038/s41467-020-19060-w⟩ Nature Communications, 2020, 11 (1), pp.5239. ⟨10.1038/s41467-020-19060-w⟩ Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-19060-w⟩ |
| Popis: | 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. Depending on the cell cycle stage, cells can repair their genome via different pathways. Here the authors reveal mechanistic insights into repair of double strand breaks induced during G1 in an error-prone manner by Pol θ-dependent and PARP1-independent alt NHEJ during the SG2/M phases of the cell cycle |
| Databáze: | OpenAIRE |
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