title: MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection.
abstract: Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3' telomeric overhangs, indicating that MAD2L2 inhibits 5' end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1 and PTIP. Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5' end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres. MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8, RNF168, 53BP1 and RIF1, but not on PTIP, REV1 and REV3, the latter two acting with MAD2L2 in translesion synthesis. Together, our data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5' end resection downstream of RIF1.
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Vera
authors: V
authors: Boersma
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Nathalie
authors: N
authors: Moatti
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Sandra
authors: S
authors: Segura-Bayona
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Marieke H
authors: MH
authors: Peuscher
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Jaco
authors: J
authors: van der Torre
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Brigitte A
authors: BA
authors: Wevers
authors: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors: Alexandre
authors: A
authors: Orthwein
authors: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.|Department of Molecular Genetics, University of Toronto, ON M5S 3E1, Canada.
authors: Daniel
authors: D
authors: Durocher
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Jacqueline J L
authors: JJL
authors: Jacobs
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D059766:DNA End-Joining Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D064246:Mad2 Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D059767:Recombinational DNA Repair / Q000235:genetics; D012097:Repressor Proteins; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; C486521:RNF8 protein, human; D012097:Repressor Proteins; C492743:Rif1 protein, human; C498301:TP53BP1 protein, human; D034501:Telomere-Binding Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes