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Molecular and Cellular Biology, October 2005, p. 8656-8668, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8656-8668.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Centrosomal Microtubule Nucleation Activity Is Inhibited by BRCA1-Dependent Ubiquitination

Satish Sankaran,1 Lea M. Starita,1 Aaron C. Groen,2 Min Ji Ko,3 and Jeffrey D. Parvin1*

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 {gamma}-tubulin with centrosomes. We find that modification of either of two specific lysine residues (Lys-48 and Lys-344) of {gamma}-tubulin, a known substrate for BRCA1-dependent ubiquitination activity, led to centrosome hyperactivity. Interestingly, mutation of {gamma}-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.

* Corresponding author. Mailing address: Brigham and Women's Hospital, NRB 630, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 525-4406. Fax: (617) 525-4422. E-mail: jparvin{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, October 2005, p. 8656-8668, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8656-8668.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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