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Molecular and Cellular Biology, October 2004, p. 8457-8466, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8457-8466.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

BRCA1-Dependent Ubiquitination of {gamma}-Tubulin Regulates Centrosome Number

Lea M. Starita,1 Yuka Machida,1 Satish Sankaran,1 Joshua E. Elias,2 Karen Griffin,1 Brian P. Schlegel,1,{dagger} Steven P. Gygi,2 and Jeffrey D. Parvin1*

Department of Pathology, Brigham and Women's Hospital,1 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts2

Received 5 February 2004/ Returned for modification 9 March 2004/ Accepted 21 June 2004

Proper centrosome duplication and spindle formation are crucial for prevention of chromosomal instability, and BRCA1 plays a role in this process. In this study, transient inhibition of BRCA1 function in cell lines derived from mammary tissue caused rapid amplification and fragmentation of centrosomes. Cell lines tested that were derived from nonmammary tissues did not amplify the centrosome number in this transient assay. We tested whether BRCA1 and its binding partner, BARD1, ubiquitinate centrosome proteins. Results showed that centrosome components, including {gamma}-tubulin, are ubiquitinated by BRCA1/BARD1 in vitro. The in vitro ubiquitination of {gamma}-tubulin was specific, and function of the carboxy terminus was necessary for this reaction; truncated BRCA1 did not ubiquitinate {gamma}-tubulin. BRCA1/BARD1 ubiquitinated lysines 48 and 344 of {gamma}-tubulin in vitro, and expression in cells of {gamma}-tubulin K48R caused a marked amplification of centrosomes. This result supports the notion that the modification of these lysines in living cells is critical in the maintenance of centrosome number. One of the key problems in understanding the biology of BRCA1 has been the identification of a specific target of BRCA1/BARD1 ubiquitination and its effect on mammary cell biology. The results of this study identify a ubiquitination target and suggest a biological impact important in the etiology of breast cancer.

* Corresponding author. Mailing address: Brigham and Women's Hospital, Department of Pathology, 75 Francis St., Boston, MA 02115. Phone: (617) 525-4406. Fax: (617) 525-4422. E-mail: jparvin{at}rics.bwh.harvard.edu.

{dagger} Present address: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.

Molecular and Cellular Biology, October 2004, p. 8457-8466, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8457-8466.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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