title: Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection.
abstract: The BRCA1 tumor suppressor plays an important role in homologous recombination (HR)-mediated DNA double-strand-break (DSB) repair. BRCA1 is phosphorylated by Chk2 kinase upon γ-irradiation, but the role of Chk2 phosphorylation is not understood. Here, we report that abrogation of Chk2 phosphorylation on BRCA1 delays end resection and the dispersion of BRCA1 from DSBs but does not affect the assembly of Mre11/Rad50/NBS1 (MRN) and CtIP at DSBs. Moreover, we show that BRCA1 is ubiquitinated by SCF(Skp2) and that abrogation of Chk2 phosphorylation impairs its ubiquitination. Our study suggests that BRCA1 is more than a scaffold protein to assemble HR repair proteins at DSBs, but that Chk2 phosphorylation of BRCA1 also serves as a built-in clock for HR repair of DSBs. BRCA1 is known to inhibit Mre11 nuclease activity. SCF(Skp2) activity appears at late G1 and peaks at S/G2, and is known to ubiquitinate phosphodegron motifs. The removal of BRCA1 from DSBs by SCF(Skp2)-mediated degradation terminates BRCA1-mediated inhibition of Mre11 nuclease activity, allowing for end resection and restricting the initiation of HR to the S/G2 phases of the cell cycle.
authors: a Department of Molecular Medicine ; University of Texas Health Science Center at San Antonio ; San Antonio , TX USA.
authors: Balaji
authors: B
authors: Parameswaran
authors: Huai-Chin
authors: HC
authors: Chiang
authors: Yunzhe
authors: Y
authors: Lu
authors: Julia
authors: J
authors: Coates
authors: Chu-Xia
authors: CX
authors: Deng
authors: Richard
authors: R
authors: Baer
authors: Hui-Kuan
authors: HK
authors: Lin
authors: Rong
authors: R
authors: Li
authors: Tanya T
authors: TT
authors: Paull
authors: Yanfen
authors: Y
authors: Hu
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism*; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D051716:Replication Protein A / Q000378:metabolism; D013997:Time Factors; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D019313:BRCA1 Protein; D046912:Multiprotein Complexes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051716:Replication Protein A; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
keywords: BRCA1; BRCA1, Breast Cancer Susceptibility Gene 1; DNA double-strand break repair; DSB, Double-Strand Break; HR, homologous Recombination; MRN, Mre11-Rad50-Nbs1 complex; NHEJ, Non-Homologous End Joining; SCF; SCF, Skp1-Cul1-F box protein complex; cell cycle; end-resection