BRCA1 Phosphorylation by Aurora-A in the Regulation of G2 to M Transition

Mutsuko Ouchi, Nobuko Fujiuchi, Kaori Sasai, Hiroshi Katayama, Yohji A. Minamishima, Pat P. Ongusaha, Chuxia Deng, Subrata Sen, Sam W. Lee, Toru Ouchi

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Abstract

Aurora-A/BTAK/STK15 localizes to the centrosome in the G2-M phase, and its kinase activity regulates the G2 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 G2-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 Ser308 of BRCA1 is phosphorylated by Aurora-A in vitro. Antiphospho-specific antibodies against Ser308 of BRCA1 demonstrated that Ser308 is phosphorylated in vivo. Phosphorylation ofSer308 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 Ser308, and transient infection of adenovirus Aurora-A increased Ser308 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 G2 arrest induced by DNA damage. We propose that BRCA1 phosphorylation by Aurora-A plays a role in G2 to M transition of cell cycle.

Original languageEnglish
Pages (from-to)19643-19648
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number19
DOIs
Publication statusPublished - 2004 May 7

ASJC Scopus subject areas

  • Biochemistry

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    Ouchi, M., Fujiuchi, N., Sasai, K., Katayama, H., Minamishima, Y. A., Ongusaha, P. P., Deng, C., Sen, S., Lee, S. W., & Ouchi, T. (2004). BRCA1 Phosphorylation by Aurora-A in the Regulation of G2 to M Transition. Journal of Biological Chemistry, 279(19), 19643-19648. https://doi.org/10.1074/jbc.M311780200