Characterization of a novel trans-activation domain of BRCA1 that functions in concert with the BRCA1 C-terminal (BRCT) domain

Mutations in the breast cancer susceptibility gene, BRCA1, account for a significant proportion of hereditary breast and ovarian cancers. The BRCA1 C-terminal (BRCT) domain, which can activate transcription when fused to a heterologous DNA binding domain, is required for BRCA1 function in suppression of tumorigenesis. Here, we provide evidence for a new activation domain in BRCA1 that lies adjacent to the BRCT domain. We name the two domains AD1 and AD2, respectively. Like AD2, the newly discovered AD1 can act independently as an activation domain in both yeast and human cells. However, unlike AD2, AD1 activity in mammalian cells is cell type context-dependent. Furthermore, combination of these two domains in mammalian cells can result in a robust synergy in transcriptional activation. A highly conserved coiled-coil motif in AD1 is required for the cooperative transcription activation. Interestingly, the functional cooperativity between AD1 and AD2 is absent in certain breast and ovarian cancer cell lines, although each domain can still activate transcription. Therefore, the differential and cooperative actions of the two activation modules may contribute to the heterogeneous risk of BRCA1 mutations in different tissues.