Linking Breast Cancer to Chromatin Remodeling

申请人描述：BRCA1基因的种系突变使个体易患乳腺癌和卵巢癌。尽管BRCA1参与转录控制和DNA链断裂修复，但其确切功能尚不清楚。我们的实验室主要研究核多蛋白复合物的功能。我们假设，brca1复合体的纯化和它们的组成和正常功能的确定将使我们了解它们在恶性转化中的作用。我们从HeLa细胞中纯化了一个含有brca1的复合体，并鉴定出它的一些成分是染色质重塑复合体SWI/SNF的亚基。我们假设BRCA1蛋白通过SWI/SNF复合体发挥其生物学功能。这三个Aims旨在提供BRCA1-SWI/SNF复合体的全面物理和功能表征。目的1将确定BRCA1复合体的剩余成分，并描述将开始定义BRCA1复合体中单个蛋白质功能的实验。目的2描述了BRCA1 -SWI/SNF复合物在雌激素信号传导中的详细功能分析。Aim 3通过分析BRCA1-SWI/SNF复合体在肿瘤抑制中的作用以及该复合体参与DNA修复来扩展这项工作。

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.