Roles for NBS1 in alternative nonhomologous end-joining of V(D)J recombination intermediates.
Recent work has highlighted the importance of alternative, error-prone mechanisms for joining DNA double-strand breaks (DSBs) in mammalian cells. These noncanonical, nonhomologous end-joining (NHEJ) pathways threaten genomic stability but remain poorly characterized. The RAG postcleavage complex normally prevents V(D)J recombination-associated DSBs from accessing alternative NHEJ. Because the MRE11/RAD50/NBS1 complex localizes to RAG-mediated DSBs and possesses DNA end tethering, processing, and joining activities, we asked whether it plays a role in the mechanism of alternative NHEJ or participates in regulating access of DSBs to alternative repair pathways. We find that NBS1 is required for alternative NHEJ of hairpin coding ends, suppresses alternative NHEJ of signal ends, and promotes proper resolution of inversional recombination intermediates. These data demonstrate that the MRE11 complex functions at two distinct levels, regulating repair pathway choice (likely through enhancing the stability of DNA end complexes) and participating in alternative NHEJ of coding ends.
Department of Pathology, The Helen L and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine and , New York University School of Medicine, New York, NY 10016, USA.
Ludovic
L
Deriano
Travis H
TH
Stracker
Annalee
A
Baker
John H J
JH
Petrini
David B
DB
Roth
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology; D017766:Acid Anhydride Hydrolases; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology; D045643:DNA Repair Enzymes / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D004720:Endonucleases; D000076228:MRE11 Homologue Protein; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011493:Protein Kinase C / Q000235:genetics; D011995:Recombination, Genetic; D045567:VDJ Recombinases / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D011493:Protein Kinase C; D045567:VDJ Recombinases; D004720:Endonucleases; D000076228:MRE11 Homologue Protein; C473337:Dclre1c protein, mouse; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes