Functional characterization of the tumor suppressor BRCA1

BRCA1 is a tumor suppressor involved in Breast and ovarian cancer encoded by a 1863 amino acid protein. The strongest lead for a biological function of BRCA1 is that of a role in either DNA repair per se or in the regulation of the response to DNA damage. Other work has also implicated a role of BRCA1 in the regulation of transcription in some unknown capacity. Work in Animals have shown that BRCA1 is required for embryonic proliferation, that BRCA1 deficient cells display genomic instability and that BRCA1 deficiency leads to a severe proliferative defect. My work has attempted to elucidate the molecular functions of BRCA1. Early work in our lab showed that BRCA1 could possibly be a transcription factor. Assuming that this would be true, we set out to identify the coactivators of BRCA1. Thus we found that p300 and CBP, the histone acetyltransferases formed a complex with BRCA1 and were able to modulate the activity of BRCA1 in the transcription of artificial reporter constructs as well as the viral Moloney murine leukemia virus (MLV) and Rous Sarcoma Virus (RSV) long terminal repeat (LTR) promoters. This also prompted us to investigate if BRCA1 was a classical transcription factor in biding to these promoters. To our surprise, our work showed that BRCA1 bound DNA nonspecifically and thus we considered it unlikely that BRCA1 could be classical transcription factor and thus had to modulate the activity of promoters in some more general fashion. This led us to attempt to see whether BRCA1 was working at the chromatin level. It was in this way that we found that BRCA1 was part of the hSWI/SNF complex. We showed that the hSWI/SNF complex is required for BRCA1 mediated resistance to ionizing radiation. At the mechanistic level we found that BARD1,a binding partner for BRCA1 was able to cooperate with BRCA1 in the ubiquitin ligase activity.