MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks.
The Mre11-Rad50-Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of antigen receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during lymphocyte antigen receptor gene assembly.
Helmink
Beth A
BA
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Bredemeyer
Andrea L
AL
Lee
Baeck-Seung
BS
Huang
Ching-Yu
CY
Sharma
Girdhar G
GG
Walker
Laura M
LM
Bednarski
Jeffrey J
JJ
Lee
Wan-Ling
WL
Pandita
Tej K
TK
Bassing
Craig H
CH
Sleckman
Barry P
BP
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D033481:Chromosomes, Mammalian / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D004789:Enzyme Activation; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D016374:Oncogene Proteins v-abl / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011995:Recombination, Genetic / Q000235:genetics; D012190:Retroviridae; D013950:Thymus Gland / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors; D050441:VDJ Exons / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D016374:Oncogene Proteins v-abl; D025521:Tumor Suppressor Proteins; C064658:RAG-1 protein; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes