The breast cancer tumor suppressor BRCA1 contains two highly conserved functional domains at its termini: the N-terminal RING domain and the C-terminal BRCT motifs. Human genetics studies suggest that both of these domains are important for BRCA1 tumor suppression functions. It is believed that the major roles of BRCA1 are involved in the maintenance of genomic stability, which is at least partially mediated by its involvement in DNA damage repair and cell cycle checkpoint control. Several years ago, we and others demonstrated that the C-terminal BRCT domain is a phospho-peptide binding domain. Subsequently we and others have shown that BRCA1 uses its BRCT domain to form three independent subcomplexes. These complexes have been named respectively BRCA1-A, BRCA1-B and BRCA1-C complexes. The BRCA1-A complex consists of RAP80, CCDC98/ABRAXAS, BRCC36, BRCC45 and MERIT40/NBA1. This complex is mainly involved in the stable accumulation of BRCA1 at sites of DNA double-strand breaks. The BRCA1-B complex contains DNA helicase BACH1 and topoisomerase II-binding protein 1 (TOPBP1). This complex is likely to act in S phase and regulate S phase progression in response to DNA damage. The BRCA1-C complex comprises CtIP and MRE11-RAD50-NBS1 (MRN) complex, which plays an essential role in damage detection, ATM activation and DNA damage repair. The framework, that BRCA1 exerts its tumor suppression functions by its participation in multiple BRCA1-containing protein complexes, has been established. In this proposal, we will further study the regulations and functions of BRCA1. We propose to: 1) explore how BRCA1-A complex and its associated DUB activity participate in the maintenance of genomic stability and tumor suppression; 2) determine the roles of BRCA1 RING domain and its E3 ligase activity in DNA damage repair; 3) identify and study new BRCA1/BARD1-associated protein complexes involved in DNA damage response and tumor suppression.
Breast cancer tumor suppressor BRCA1 interacts with many binding partners and participates in a variety of cellular processes to ensure genomic integrity. In this grant application, we will study the regulation and function of BRCA1 E3 ligase activity and BRCA1-associated protein complexes in DNA damage response. We hope that these studies will reveal the molecular mechanisms underlying BRCA1 tumor suppressor functions.
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