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Beschreibung

Breast cancer type 1 susceptibility protein (UniProt: P38398, also known as EC:2.3.2.27, RING finger protein 53, RING-type E3 ubiquitin transferase BRCA1) is encoded by the BRCA1 (also known as RNF53) gene (Gene ID: 672) in human. BRCA1 and BRCA2 are important in maintaining genomic stability by promoting efficient and precise repair of double-strand breaks. BRCA1 is expressed in all cells and plays a broader role in various cellular processes in response to DNA damage. It promotes the protection of nascent DNA at stalled replication forks independently of the canonical BRCA1-PALB2 interaction. Its recruitment to DNA damage sites is mediated by ABRAXAS1 and the BRCA1-A complex. BRCA1 contains two BRCT domains (aa 1642-1736 and 1756-1855) that recognize and bind phosphorylated pSXXF motif on proteins. The interaction with the phosphorylated pSXXF motif of ABRAXAS1 recruits BRCA1 at DNA damage sites. BRCA1 is reported to exist as a heterodimeric complex with BARD1, a structurally related protein that also contains a N-terminal RING-finger domain and two C-terminal BRCT motifs. This heterodimer regulates the localization and loading of RAD51 at break sites through PALB2-BRCA2. Their association is mediated through their respective RING domains, and together they exhibit E3 ubiquitin ligase activity, which can be disrupted by mutations within the RING domain of BRCA1. BRCA1 and BARD1 are shown to be phosphorylated at residues that are located close to the site of interaction between BARD1 and RAD51 (Ser148 on BARD1 and Ser114 on BRCA1) and Ser114 phosphorylation promotes BRCA1 interaction with PIN1. PIN1 increases interactions between the BRCA1-BARD1 complex and RAD51 resulting in recruitment of RAD51 to stalled replication forks and enhance protection of the nascent DNA strand. Cells lacking BRCA1 show defects in DNA repair by homologous recombination. Mutations in BRCA1 gene have been linked to breast and ovarian cancers. A vast majority of inherited breast cancers result from mutations in the BRCA 1 gene. Male subjects with BRCA1 mutations exhibit about 3-fold increase in risk of prostate cancer. (Ref.: Daza-Martin, M., et al. (2019). Nature. 571(7766), 521-527, Gudumundsdottir, K., and Ashworth, A. (2006). Oncogene 25, 5864-5874).