RAP80 and BRCA1 PARsylation protect chromosome integrity by preventing retention of BRCA1-B/C complexes in DNA repair foci

Abstract

BRCA1 promotes error-free, homologous recombination-mediated repair (HRR) of DNA double-stranded breaks (DSBs). When excessive and uncontrolled, BRCA1 HRR activity promotes illegitimate recombination and genome disorder. We and others have observed that the BRCA1-associated protein RAP80 recruits BRCA1 to postdamage nuclear foci, and these chromatin structures then restrict the amplitude of BRCA1-driven HRR. What remains unclear is how this process is regulated. Here we report that both BRCA1 poly-ADP ribosylation (PARsylation) and the presence of BRCA1-bound RAP80 are critical for the normal interaction of BRCA1 with some of its partners (e.g., CtIP and BACH1) that are also known components of the aforementioned focal structures. Surprisingly, the simultaneous loss of RAP80 and failure therein of BRCA1 PARsylation results in the dysregulated accumulation in these foci of BRCA1 complexes. This in turn is associated with the intracellular development of a state of hyper-recombination and gross chromosomal disorder. Thus, physiological RAP80-BRCA1 complex formation and BRCA1 PARsylation contribute to the kinetics by which BRCA1 HRR-sustaining complexes normally concentrate in nuclear foci. These events likely contribute to aneuploidy suppression.

RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage

“…Thus, it has been proposed that the BRCA1-ABRAXAS-RAP80 (BRCA1-A) complex is responsible for localizing PALB2 to DSBs 6 . However, several reports have demonstrated that the BRCA1-RAP80 association reduces cellular HR activity 7 , 8 . Moreover, RAP80 depletion was shown to have little effect on RAD51 foci formation 7 , making the role of RAP80-ABRAXAS in recruiting BRCA1-P ambiguous.…”

Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells

“…In addition to its direct role in PARylating sites of DNA damage, PARP has also been documented to PARylate and modify the function of numerous DNA repair proteins, including ATM and BRCA1 [12]. For instance, BRCA1 PARylation prevents dysfunctional HR repair and chromosomal rearrangements [46]. Considering our observation that DFMO affects PARP activity, it is possible that perturbing polyamine levels also alters the activity and function of ATM and BRCA1 by reducing PARylation on these key components of the DNA repair response.…”

Identification and Validation of Three Hub Genes Involved in Cell Proliferation and Prognosis of Castration-Resistant Prostate Cancer

“…It is worth noting that the NUF2 expression level was positively correlated with the expression levels of CENPI and KNTC1. BRCA1 is a major homologous recombination-mediated repair (HRR) support protein that can work in conjunction with certain chaperone proteins (including RAD51, CTIP, and BRIP1), and it promotes the proper HRR process to regulate the stability of chromosomes [ 64 ]. Its expression level also showed a clear correlation with the expression level of KNTC1.…”