Aurora-A/BTAK/STK15 localizes to the centrosome in the G(2)-M phase, and its kinase activity regulates the G(2) to M transition of the cell cycle. Previous studies have shown that the BRCA1 breast cancer tumor suppressor also localizes to the centrosome and that BRCA1 inactivation results in loss of the G(2)-M checkpoint. We demonstrate here that Aurora-A physically binds to and phosphorylates BRCA1. Biochemical analysis showed that BRCA1 amino acids 1314-1863 binds to Aurora-A. Site-directed mutagenesis indicated that Ser(308) of BRCA1 is phosphorylated by Aurora-A in vitro. Anti-phospho-specific antibodies against Ser(308) of BRCA1 demonstrated that Ser(308) is phosphorylated in vivo. Phosphorylation of Ser(308) increased in the early M phase when Aurora-A activity also increases; these effects could be abolished by ionizing radiation. Consistent with these observations, acute loss of Aurora-A by small interfering RNA resulted in reduced phosphorylation of BRCA1 Ser(308), and transient infection of adenovirus Aurora-A increased Ser(308) phosphorylation. Mutation of a single phosphorylation site of BRCA1 (S308N), when expressed in BRCA1-deficient mouse embryo fibroblasts, decreased the number of cells in the M phase to a degree similar to that with wild type BRCA1-mediated G(2) arrest induced by DNA damage. We propose that BRCA1 phosphorylation by Aurora-A plays a role in G(2) to M transition of cell cycle.
PubMed ID: 14990569
Article link: J Biol Chem.
Grant support: CA 79892 NCI NIH HHS , CA 79892 NCI NIH HHS , CA 79892 NCI NIH HHS , CA 79892 NCI NIH HHS , CA 79892 NCI NIH HHS , CA 79892 NCI NIH HHS , CA 90631 NCI NIH HHS , CA 90631 NCI NIH HHS , CA 90631 NCI NIH HHS , CA 90631 NCI NIH HHS , CA 90631 NCI NIH HHS , CA 90631 NCI NIH HHS
Genes referenced: aurka brca1