Linking Breast Cancer to Chromatin Remodeling

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APPLICANT'S DESCRIPTION: Germ line mutations in the BRCA1 gene predispose individuals to breast and ovarian cancer. Although, BRCA1 has been implicated in transcriptional control and DNA strand break repair, its precise function is unknown. Our laboratory is focused on the function of nuclear multiprotein complexes. We hypothesize that purification of the BRCA 1 complex(es) and determination of their composition and normal functions will allow us to understand their roles in malignant transformation. We have purified a BRCA1-containing complex from HeLa cells and identified a number of its components as subunits of the chromatin remodeling complex SWI/SNF. We hypothesize that the BRCA1 protein exerts its biological functions through the SWI/SNF complex. The three Aims are designed to provide a thorough physical and functional characterization of the BRCA1-SWI/SNF complex. Aim 1 will identify the remaining components of the BRCA1 complex, and describes experiments that will begin to define the function of the individual proteins in the BRCA1 complex. Aim 2 describes a detailed functional analysis of the BRCA1 -SWI/SNF complex in estrogen signaling. Aim 3 extends the work by analyzing the role of the BRCA1-SWI/SNF complex in tumor suppression and the complex's involvement in DNA repair.