Recent identification of the breast and ovarian cancer susceptibility genes, BRCA1, promises to generate a wealth of information concerning breast and ovarian cancer cell biology. A full understanding of the cellular role of BRCA1 requires a detailed understanding of both the function and the structure of the protein and its interacting partners. BRCA1 is a large, complex protein which is undoubtedly comprised of a multiplicity of functional domains. The overall goals of this project are to elucidate the domain structure of BRCA1, to define the three- dimensional structures of such domains, and to characterize the interactions of the domains with cellular macromolecular partners that interact specifically with BRCA1 in vivo. A broad biochemical and biophysical approach will be undertaken, involving techniques such as multidimensional NMR, proteolytic mapping by MALDI-MS, and fluorescence. We propose to compare the properties and structures of wild-type domains with those harboring known cancer-predisposing mutations. The resulting description of the biochemical and structural properties of functional domains of BRCA1 will contribute significantly to the challenging task of discovering and understanding both the normal and pathological roles of BRCA1.
