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Identification of a -Tubulin-binding Domain in BRCA1¹

Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112

We previously reported (L-C. Hsu and R. L. White, Proc. Natl. Acad. Sci. USA, 95: 12983–12988, 1998) that hypophosphorylated BRCA1 is associated with mitotic centrosomes in vivo, perhaps through its interaction with -tubulin. In vitro evidence presented here indicates that full-length BRCA1 protein generated by in vitro translation interacts with -tubulin. A specific domain of BRCA1 protein, BRCA1 fragment no. 3 (BF3; amino acids 504–803), is both necessary and sufficient to bind -tubulin. BF3 and -tubulin coimmunoprecipitated when coexpressed in cells. In addition, expression of BF3 interfered with the interaction between BRCA1 and -tubulin. Stable transformants of COS-7 cells that overexpressed BF3 showed a reduced growth rate partly because of increased apoptosis. Furthermore, overexpression of BF3 in COS-7 cells results in the accumulation of mitotic cells with multiple centrosomes and abnormal spindles. Okadaic acid, an inhibitor of protein phosphatases types 1 and 2A, induces hyperphosphorylation of BRCA1, a reduction of both BRCA1 and -tubulin associated with mitotic centrosomes, and an accumulation of abnormal spindle formation. Thus, attenuating the interaction between BRCA1 and -tubulin, and their association with mitotic centrosomes, may induce an increase of aneuploid cell population and contribute to tumorigenesis.

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