The second BRCT domain of BRCA-1 proteins interacts with p53 and stimulates transcription from the p21(WAF1/CIP1) promoter

Inherited mutations in the breast and ovarian cancer susceptibility gene BR CA1 are associated with high risk for developing breast and ovarian cancers . Several studies link BRCA1 to transcriptional regulation, DNA repair, apo ptosis and growth/tumor suppression. BRCA1 associates with p53 and stimulat es transcription in both p53 dependent and p53-independent manners. BRCA1 s plice variants BRCA1a (p110) and BRCA1b (p100) associates with CBP/p300 co- activators. Here we show that BRCA1a and BRCA1b proteins stimulate p53-depe ndent transcription from the p21(WAF1/CIP1) promoter. In addition, the C-te rminal second BRCA1 (BRCT) domain is sufficient for p53 mediated transactiv ation of the p21 promoter. Previous studies emphasized the importance of th e BRCT domain, which shows homology with p53 binding protein (53BP1), in tr anscriptional activation, growth inhibition and tumor suppression. Our find ings demonstrate an additional function for this domain in protein-protein interaction and co-activation of p53. We also found that BRCA1a and BRCA1b proteins interact with p53 in vitro and in vivo. The p53 interaction domain of BRCA1a/1b maps, in vitro, to the second BRCT domain (aa 1760-1863). The BRCT domain binds to the central domain of p53 which is required for seque nce specific DNA binding. These results demonstrate for the first time the presence of a second p53 interaction domain in BRCA1 proteins and suggests that BRCA1a and BRCA1b proteins, like BRCA1, function as p53 co-activators. This BRCT domain also binds in vitro to CBP. These results suggest that on e of the mechanisms by which BRCA1 proteins function is through recruitment of CBP/p300 associated HAT/FAT activity for acetylation of p53 to specific promoters resulting in transcriptional activation.