Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection

The BRCA1 tumor suppressor plays an important role in homologous recombination(HR)-mediated DNA double-strand-break (DSB) repair. BRCA1 is phosphorylated by Chk2 kinaseupon γ-irradiation, but the role of Chk2 phosphorylation is not understood. Here, wereport that abrogation of Chk2 phosphorylation on BRCA1 delays end resection and thedispersion 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 andthat abrogation of Chk2 phosphorylation impairs its ubiquitination. Our study suggeststhat BRCA1 is more than a scaffold protein to assemble HR repair proteins at DSBs, butthat 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 atlate G1 and peaks at S/G2, and is known to ubiquitinate phosphodegron motifs. The removalof BRCA1 from DSBs by SCF^Skp2-mediated degradation terminates BRCA1-mediatedinhibition of Mre11 nuclease activity, allowing for end resection and restricting theinitiation of HR to the S/G2 phases of the cell cycle.