MRE11-RAD50-NBS1 complex dictates DNA repair independent of H2AX.
DNA double-strand breaks (DSBs) represent one of the most serious forms of DNA damage that can occur in the genome. Here, we show that the DSB-induced signaling cascade and homologous recombination (HR)-mediated DSB repair pathway can be genetically separated. We demonstrate that the MRE11-RAD50-NBS1 (MRN) complex acts to promote DNA end resection and the generation of single-stranded DNA, which is critically important for HR repair. These functions of the MRN complex can occur independently of the H2AX-mediated DNA damage signaling cascade, which promotes stable accumulation of other signaling and repair proteins such as 53BP1 and BRCA1 to sites of DNA damage. Nevertheless, mild defects in HR repair are observed in H2AX-deficient cells, suggesting that the H2AX-dependent DNA damage-signaling cascade assists DNA repair. We propose that the MRN complex is responsible for the initial recognition of DSBs and works together with both CtIP and the H2AX-dependent DNA damage-signaling cascade to facilitate repair by HR and regulate DNA damage checkpoints.
Yuan
Jingsong
J
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Chen
Junjie
J
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D017766:Acid Anhydride Hydrolases; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000071857:Tumor Suppressor p53-Binding Protein 1
D018528:ATP-Binding Cassette Transporters; D017766:Acid Anhydride Hydrolases; D019313:BRCA1 Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D045643:DNA Repair Enzymes; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D000076228:MRE11 Homologue Protein; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C492913:BRCA1 protein, human; C501070:RBBP8 protein, mouse; C468783:H2AX protein, human; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; C410741:RBBP8 protein, human; C112158:RAD50 protein, human; C495198:Rad50 protein, mouse; C475961:gamma-H2AX protein, mouse