The mechanism of action of the BRCA1 tumor suppressor gene remains unclear. Following DNA damage BRCAI localizes to subnuclear foci along with other proteins involved in DNA repair. BRCA1 rescues survival of BRCA1-deficient cells that are highly sensitive to DNA damage. There is also evidence that BRCA1 is involved in regulating transcription of genes through interactions with transcriptional activators, repressors and chromatin remodeling proteins. We have shown that BRCA1 can stabilize and coactivate p53-dependent gene expression. Because overexpression of BRCA1 stabilizes p53 but does not lead to apoptosis in most cell lines, but rather seems to promote cell survival, we investigated the targets downstream of p53 stabilization. BRCA1 appears to direct a unique (restricted) transcriptional response leading to upregulation of cell cycle arresting genes such as p21 and GADD45, and DNA repair genes such as p53R2 and the Xeroderma Pigmentosum group E DNA Damage Binding protein DDB2, but not apoptosis promoting genes. DDB2 is regulated by BRCA1 through p53 and BRCA1 appears to be required for DDB2 induction following UV exposure. We propose a hypothesis that following DNA damage rapid BRCA1 protein-DNA repair protein interactions and changes in localization lead to initiation of repair whereas a slower transcriptional response leads to maintenance and enhancement of repair. Our goals are:
Specific Aim #1 : Investigate which p53 targets BRCA1 is required for and how BRCA1 directs p53 towards arrest and repair and away from death.
Specific Aim #2 : Evaluate the contribution of DDB2 and transcription towards the repair activity of BRCA1 and breast cancer, and Specific Aim #3: Determine the structural features within BRCA 1 that are required for activation of p53 targets. Our studies will increase our understanding of the mechanism of action of BRCA1 and may provide novel strategies for therapeutic design, for example by targeting DDB2.
| Navaraj, Arunasalam; Finnberg, Niklas; Dicker, David T et al. (2009) Reduced cell death, invasive and angiogenic features conferred by BRCA1-deficiency in mammary epithelial cells transformed with H-Ras. Cancer Biol Ther 8:2417-44 |
| Navaraj, Arunasalam; Mori, Toshio; El-Deiry, Wafik S (2005) Cooperation between BRCA1 and p53 in repair of cyclobutane pyrimidine dimers. Cancer Biol Ther 4:1409-14 |
| Benezra, Miriam; Chevallier, Nathalie; Morrison, Debra J et al. (2003) BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65/RelA subunit. J Biol Chem 278:26333-41 |
