The BRCA1-dependent ubiquitin ligase, gamma-tubulin, and centrosomes.

Mutation of the breast and ovarian cancer specific tumor suppressor, BRCA1, results in supernumerary and hyperactive centrosomes, which in turn likely contribute to the aneuploidy evident in breast cancer cells. The BRCA1-dependent ubiquitin ligase activity is required for the regulation of centrosome function, and among its substrates is gamma-tubulin. Data suggest that during S and G2 phases of the cell cycle, the normal function of BRCA1 directs the ubiquitination of gamma-tubulin, resulting in inhibition of centrosome microtubule nucleation function and blocking of centrosome reduplication. Loss of BRCA1 activity, as occurs in breast cancer cells, would result in centrosomes that are unrestrained, leading to the hyperactive and over-duplicated centrosomes often observed in breast cancer cells. The current knowledge of BRCA1 regulation of centrosomes will be discussed in this focused review, and it will be suggested that this function is important for the tumor suppression phenotype of BRCA1. (c) 2009 Wiley-Liss, Inc.