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BRCA1, cloned during the search for genes responsible for hereditary breast and ovarian cancers, has been implicated in numerous cellular processes including DNA repair, cell cycle checkpoint activation, transcriptional regulation and chromatin remodeling. With respect to one of its roles in transcriptional regulation, BRCA1 has been shown to stabilize the tumor suppressor p53 protein. Increased expression/stability of p53 normally results in increased expression of p53-regulated pro-apoptotic genes and therefore, increased apoptosis. Interestingly, however, microarray studies have demonstrated that overexpression of BRCA1 results in the expression of p53-regulated cell cycle arrest genes, but not p53-regulated pro-apoptotic genes. Given that stabilization of p53 normally correlates with increased expression of pro-apoptotic genes, it is of great interest to understand how BRCA1 directs p53 to preferentially induce expression of genes involved in cell cycle delay and damage repair but not pro-apoptotic targets. We have been using chromatin immunoprecipitation (ChIP) assays to investigate proteins present at the promoters of genes involved in cell cycle arrest vs. those present at the promoters of genes involved in apoptosis. Surprisingly, p53 appears to be present at the DR5 promoter (a pro-apoptotic target) as well as at the p21 promoter (cell cycle arrest target) in the presence of BRCA1. In response to DNA damage, p53 is stabilized and activated by a plethora of post-translational modifications. Therefore, we have also examined the post-translational modifications induced by exogenous expression of BRCA1. Both adriamycin and exogenous BRCA1 expression appear to have the same ability to phosphorylate and acetylate p53. Therefore, we are currently exploring the hypothesis that BRCA1 exerts a repressive function at the apoptotic promoters.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]