BRCA1 signals ARF-dependent stabilization and coactivation of p53

The hereditary breast and ovarian tumor suppressor BRCA1 can activate p53-d ependent gene expression. We show here that BRCA1 increases p53 protein lev els through a post-transcriptional mechanism. BRCA1-stabilized p53 has incr eased sequence-specific DNA-binding and transcriptional activity, BRCA1 doe s not stabilize p53 in p14(ARF)-deficient cells. A deletion mutant of BRCA1 which inhibits p53-dependent transcription confers resistance to topoisome rase II-targeted chemotherapy, Our results suggest that BRCA1 may trigger t he p53 pathway through two potentially separate mechanisms: accumulation of p53 through a direct or indirect induction of p14(ARF) as well as direct t ranscriptional coactivation of p53, BRCA1 may also enhance chemosensitivity and repair of DNA damage through binding to and coactivation of p53.