Mechanism of BRCA1 function

BRCA1 is mutated in the germline of 20-40% of women with hereditary susceptibility to breast and ovarian cancers and meet the definition of a classic tumor suppressor gene. However, while it has been shown that BRCA1 expression and phosphorylation are cell cycle-dependent and may be responsive to DNA damage, the mechanism of BRCA1 function is unknown. In studies aimed at beginning to understand the biological role of BRCA1, we demonstrated that BRCA1 is a nuclear protein and that KLKRKRR(AA501-507) in BRCA1 is a nuclear localization signal (NLS). This signal is necessary and sufficient to guide BRCA1 into the nucleus. The NLS receptor karyopherin $\alpha$ binds to BRCA1, this interaction is dependent on the presence of the NLS. In addition, we demonstrated that the universal CDK-inhibitor p21$\rm\sp{WAF1/CIP1}$ is a target gene of BRCA1 transactivation, that BRCA1-mediated p21 expression can be independent of p53. Overexpression of BRCA1 inhibits S-phase progression only in the presence of p21. Finally, we have found BRCA1 binds to p53 in vitro and in vivo, mediated by the tetramerization domain of p53 and AA 224-500 in exon 11 of BRCA1. Functional studies provide evidence that the BRCA1-p53 interaction strongly stimulates p53-dependent transcription. In summary, our findings suggest BRCA1 is a nuclear protein that utilizes karyopherin nuclear transport machinery for its nuclear import, functions as a transcription factor that negatively control cell cycle progression through p21 induction and also works as a coactivator of p53-mediated transcription. We hypothesize that BRCA1 may be responsive to DNA damage partly through modulation of p53 function