title: RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci.
abstract: In response to DNA double-strand breaks (DSBs), BRCA1 forms biochemically distinct complexes with certain other DNA damage response proteins. These structures, some of which are required for homologous recombination (HR)-type DSB repair, concentrate at distinct nuclear foci that demarcate sites of genome breakage. Polyubiquitin binding by one of these structures, the RAP80/BRCA1 complex, is required for efficient BRCA1 focal recruitment, but the relationship of this process to the execution of HR has been unclear. We found that this complex actively suppresses otherwise exaggerated, BRCA1-driven HR. By controlling the kinetics by which other BRCA1-interacting proteins that promote HR concentrate together with BRCA1 in nuclear foci, RAP80/BRCA1 complexes suppress excessive DSB end processing, HR-type DSB repair, and overt chromosomal instability. Since chromosomal instability emerges when BRCA1 HR function is either unbridled or absent, active tuning of BRCA1 activity, executed in nuclear foci, is important to genome integrity maintenance.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yiduo
authors.initials: Y
authors.lastname: Hu
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
authors.forename: Bijan
authors.initials: B
authors.lastname: Sobhian
authors.forename: Anyong
authors.initials: A
authors.lastname: Xie
authors.forename: Elena
authors.initials: E
authors.lastname: Shestakova
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D002875:Chromosomes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins; D057809:HEK293 Cells; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D011995:Recombination, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009687:Nuclear Proteins; C466234:UIMC1 protein, human