BRCA1 A-Complex fine tunes repair functions of BRCA1

mutations in BRCA1 increase the risk of breast and ovarian cancer, but the specific pathways driving breast and ovarian cancer development in BRCA1 mutants are currently unclear [1]. Several studies have demonstrated that BRCA1 is required for cellular responses to DNA double strand breaks (DSBs) and homologous recombination (HR), although its exact role in these processes is unclear. BRCA1 contains an N-terminal RING domain and two C-terminal BRCT repeats. The BRCA1 RING domain imparts ubiquitin ligase activity to BRCA1 through interaction with its key binding partner BARD1 [2]. BRCT repeats contribute to transcriptional and DNA repair function of BRCA1, and cancer associated mutations that disrupt BRCT motif impair these activities [3]. BRCA1 forms at least 3 distinct complexes (BRCA1 A, BRCA1 B and BRCA1 C) through association of different adaptor proteins with BRCT motif. A-Complex function has been the subject of considerable research interest in the last several years, and is the focus of a study by Dever et al. in this issue of Aging [4] as well as other recent studies [5, 6]. The A-Complex consists of BRCA1 in association with the ubiquitin interacting motif (UIM) containing protein RAP80, the deubiquitinylating (DUB) enzymes BRCC36 and BRCC45, MERIT 40 , and the adaptor protein Abraxas [7-10]. The A-Complex is thought to target BRCA1 to ionising radiation (IR) inducible foci through interaction of RAP80 with K63 poly-ubiquitin chains at sites of DSBs, in particular on H2AX [7, 11-13]. This RAP80 recruiting ubiquitinylation is performed by the E2 ubiquitin conjugase Ubc13 and the E3 ligase RNF8, which are targeted to breaks by MDC1 [14-16]. The critical role of ubiquitinylation as a recruitment signal at DNA damage sites is highlighted by the hypersensitivity of Ubc13 and RNF8-deficient cells to irradiation [14-17]. The new study by Dever et al. indicates that disruption of the BRCA1 complexes through mutation in BRCT motif causes genomic instability due to an increase in recombination [4]. Specifically, the authors explored the function of the BRCA1 BRCT mutant K1702M, in which BRCT mediated phosphoprotein interactions are disrupted. They found that expression of K1702M caused radiosensitivity compared to wild-type comp-Discussion lemented BRCA1 deficient cells. Intra-chromosomal recombination is commonly assessed using a flow cytometry based DR-GFP recombination assay. Dever et al. used this method to determine that expression of the K1702M mutant was associated with elevated recombination compared to wild-type BRCA1, indicating that the K1702M mutant disrupts critical negative regulation of recombination …