title: The BRCA1-RAP80 complex regulates DNA repair mechanism utilization by restricting end resection.
abstract: The tumor suppressor protein BRCA1 is a constituent of several different protein complexes and is required for homology-directed repair (HDR) of DNA double strand breaks (DSBs). The most recently discovered BRCA1-RAP80 complex is recruited to ubiquitin structures on chromatin surrounding the break. Deficiency of any member of this complex confers hypersensitivity to DNA-damaging agents by undefined mechanisms. In striking contrast to other BRCA1-containing complexes that are known to promote HDR, we demonstrate that the BRCA1-RAP80 complex restricts end resection in S/G(2) phase of the cell cycle, thereby limiting HDR. RAP80 or BRCC36 deficiency resulted in elevated Mre11-CtIP-dependent 5' end resection with a concomitant increase in HDR mechanisms that rely on 3' single-stranded overhangs. We propose a model in which the BRCA1-RAP80 complex limits nuclease accessibility to DSBs, thus preventing excessive end resection and potentially deleterious homology-directed DSB repair mechanisms that can impair genome integrity.
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Kara A
authors.initials: KA
authors.lastname: Coleman
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000072017:Deubiquitinating Enzymes; D004706:Endodeoxyribonucleases; D016195:G2 Phase / Q000502:physiology; D042822:Genomic Instability / Q000502:physiology*; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D000076228:MRE11 Homologue Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000502:physiology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C121766:MRE11 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C466234:UIMC1 protein, human; D004706:Endodeoxyribonucleases; D000076228:MRE11 Homologue Protein; C410741:RBBP8 protein, human; C518017:BRCC3 protein, human; D000072017:Deubiquitinating Enzymes