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Centrosomal Microtubule Nucleation Activity Is Inhibited by BRCA1-Dependent Ubiquitination

Department of Pathology, Brigham and Women's Hospital,¹ Department of Systems Biology, Harvard Medical School, Boston, Massachusetts,² Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, South Korea³

Received 3 March 2005/ Returned for modification 18 April 2005/ Accepted 14 July 2005

In this study we find that the function of BRCA1 inhibits the microtubule nucleation function of centrosomes. In particular, cells in early S phase have quiescent centrosomes due to BRCA1 activity, which inhibits the association of -tubulin with centrosomes. We find that modification of either of two specific lysine residues (Lys-48 and Lys-344) of -tubulin, a known substrate for BRCA1-dependent ubiquitination activity, led to centrosome hyperactivity. Interestingly, mutation of -tubulin lysine 344 had a minimal effect on centrosome number but a profound effect on microtubule nucleation function, indicating that the processes regulating centrosome duplication and microtubule nucleation are distinct. Using an in vitro aster formation assay, we found that BRCA1-dependent ubiquitination activity directly inhibits microtubule nucleation by centrosomes. Mutant BRCA1 protein that was inactive as a ubiquitin ligase did not inhibit aster formation by the centrosome. Further, a BRCA1 carboxy-terminal truncation mutant that was an active ubiquitin ligase lacked domains critical for the inhibition of centrosome function. These experiments reveal an important new functional assay regulated by the BRCA1-dependent ubiquitin ligase, and the results suggest that the loss of this BRCA1 activity could cause the centrosome hypertrophy and subsequent aneuploidy typically found in breast cancers.

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