The BRCA1-A complex: At the edge of resection and the beauty of restraint.

Abstract

How a DNA double-strand break (DSB) is repaired by the cell is organized around a fundamental decision between DNA end protection and 5'-end resection. BRCA1 is a central regulator of this choice, promoting DNA end resection in the S and G2 phases of the cell cycle to stimulate error free repair by homologous recombination. Among BRCA1 interacting complexes involved in HR, the BRCA1-A complex occupies a distinctive and still somewhat paradoxical position. Through ABRAXAS1-dependent BRCA1 docking and RAP80-mediated recognition of ubiquitin-marked chromatin, the BRCA1-A complex contributes to BRCA1 accumulation at DSBs. Genetic and biochemical studies, however, have demonstrated that BRCA1 recruitment to breaks is not solely channeled via BRCA1-A, but is partially redundant with BARD1-mediated localization to damage-associated nucleosomes. Moreover, while loss of BRCA1-A components reduces BRCA1 foci formation at break sites, it increases CtIP/MRE11-dependent DNA end resection and mutagenic repair outcomes. Interestingly, these hyper-resection effects are also present in the absence of BRCA1, indicating a BRCA1-independent role of the BRCA1-A complex. Here, we review the available literature on the different functions of the BRCA1-A complex in DSB repair and speculate about its role as a ubiquitin-gated module that positions BRCA1 at damaged chromatin and its contribution to restraint of excessive, mutagenic DNA end resection.