Molecular mechanisms underlying the development of familial breast and ovarian cancer have become the focuses of many laboratories following the cloning of breast cancer susceptibility gene BRCA1. In the last four years since this grant was first funded, our understanding of BRCA1 has expanded at a rapid pace. BRCA1 contains two functional motifs: the N-terminal RING domain and the C-terminal BRCA1 C-terminus (BRCT) domain. We now know that the functional significance of two recognizable motifs within BRCA1. Studies from us have revealed that BRCA1 BRCT domain is a phospho-protein binding domain. Through this reversible interaction domain, BRCA1 associates with many binding-partners and participates in multiple cellular functions. We also know that the N-terminal Ring domain of BRCA1 has intrinsic E3 ubiquitin ligase activity. However, it is not clear how these two domains function together in ensuring genomic stability. Base on our preliminary studies, we propose that BRCA1 recruits its substrates through the BRCT domain, modifies these substrates via the N-terminal Ring domain-dependent ubiquitination reactions, and thus regulates diverse cellular processes. Here, we will test this hypothesis.
In Specific Aim 1, we will examine whether a known BRCA1 BRCT domain-associated protein is a direct substrate of BRCA1. In preliminary studies, we have shown that topoisomerase II alpha is ubiquitinated and regulated by BRCA1.
In Specific Aim 2, we will determine whether the interaction between topoisomerase II and BRCA1 depends on the intact BRCA1 BRCT domains and explore how this interaction is regulated in cells. We have identified one new BRCA1 BRCT domain-associated protein.
In Specific Aim 3, we will further study its interaction with BRCA1 and how this BRCA1-associated protein contributes to BRCA1 functions. Collectively, these studies will provide novel insights into the regulation and tumor suppression function of BRCA1. ? ? ?
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