Linking Breast Cancer to Chromatin Remodeling

申请人描述：BRCA 1基因的种系突变使个体易患乳腺癌和卵巢癌。虽然BRCA 1参与转录调控和DNA链断裂修复，但其确切功能尚不清楚。我们的实验室专注于核多蛋白复合物的功能。我们假设，纯化BRCA 1复合物并确定其组成和正常功能将使我们了解它们在恶性转化中的作用。我们已经从HeLa细胞中纯化了一种含有BRCA 1的复合物，并鉴定了其许多组分为染色质重塑复合物SWI/SNF的亚基。我们推测BRCA 1蛋白通过SWI/SNF复合物发挥其生物学功能。这三个目的旨在提供BRCA 1-SWI/SNF复合物的全面物理和功能表征。目标1将确定BRCA 1复合物的其余组分，并描述将开始定义BRCA 1复合物中单个蛋白质功能的实验。目的2描述了BRCA 1-SWI/SNF复合物在雌激素信号转导中的详细功能分析。目的3通过分析BRCA 1-SWI/SNF复合物在肿瘤抑制中的作用以及该复合物参与DNA修复来扩展工作。

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.