Functional Analysis of SWI/SNF chromatin remodelers

SWI/SNF 染色质重塑剂的功能分析

• 批准号: 7106507
• 负责人: HUA-YING FAN
• 金额: $ 6.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7106507
• 关键词: HeLa cells; SDS polyacrylamide gel electrophoresis; adenosine triphosphate; cell growth regulation; chromatin; conformation; crosslink; enzyme activity; enzyme substrate; gene expression; histones; hydrolysis; intermolecular interaction; mass spectrometry; nucleic acid biosynthesis; nucleic acid structure; nucleosomes; protein sequence; protein structure function; recombinant proteins; western blottings

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand how ATP-dependent chromatin-remodeling complexes regulate nuclear events, maintain normal cell growth and prevent cancer formation. Cellular transformation is often caused by aberrant expression of genes involved in growth control. Chromatin remodeling complexes function as transcription co-regulators and have been found to play a role in cell-cycle progression. BRG1 and INI1/hSNF5, two conserved subunits of SWI/SNF, appear to behave as classical tumor suppressors. Mutations in BRG1 have been found in multiple human tumor cell lines, and the INI1/hSNF5 subunit is often mutated in rhabdoid sarcomas, a very aggressive pediatric cancer. Mutations or deletions of other conserved components of human SWI/SNF complexes have also been detected in a number of chronic and acute leukemias, CNS tumors and human adenocarcinomas. Increasing numbers of ATP-dependent chromatin-remodeling complexes are being identified. Each of them has an ATPase core subunit, and some of these ATPase subunits have been demonstrated to function as motor proteins. The SWI/SNF and ISWl families are the best understood among ATP-dependent chromatin remodeling complexes. BRG1 and SNF2h are the motors for the most prominent human SWI/SNF and ISWl families, respectively. A fundamental question is how the ATP-hydrolysis activities of similar core subunits, such as BRG1 and SNF2h, can be used to accomplish distinct chromatin remodeling reactions, and how these proteins differentially contribute to regulate chromatin structure. This application proposes a detailed comparison of ATP-dependent chromatin remodeling mechanisms, and an investigation into how mechanistic differences might impact upon gene expression in vivo. Results from these experiments will increase our understanding of how different classes of remodeling mechanisms control different biological processes.

描述（由申请人提供）：该提案的长期目标是了解ATP依赖性染色质复制复合物如何调节核事件，保持正常的细胞生长并防止癌症形成。 细胞转化通常是由参与生长控制的基因的异常表达引起的。 染色质重塑络合物起着转录共调节剂的作用，并被发现在细胞周期进展中起作用。 SWI/SNF的两个保守亚基的BRG1和INI1/HSNF5似乎是经典的肿瘤抑制剂。 在多个人类肿瘤细胞系中发现了BRG1中的突变，并且INI1/HSNF5亚基通常在牙骨肉瘤（一种非常侵略性的儿科癌症）中突变。 在许多慢性和急性白血病，中枢神经系统肿瘤和人腺癌中，还检测到了人类SWI/SNF复合物的其他保守成分的突变或缺失。 正在鉴定越来越多的ATP依赖性染色质复合物。 它们每个都有一个ATPase核心亚基，其中一些ATPase亚基已被证明充当运动蛋白。 SWI/SNF和ISWL家族是ATP依赖性染色质重塑络合物中最好的理解。 BRG1和SNF2H分别是人类SWI/SNF和ISWL家族的电机。 一个基本问题是，如何使用类似核心亚基的ATP-Hydrolysyssis活性（例如BRG1和SNF2H）来完成不同的染色质重塑反应，以及这些蛋白质如何差异化有助于调节染色质结构。 该应用提出了对ATP依赖性染色质重塑机制的详细比较，并研究了机械差异如何影响体内基因表达。 这些实验的结果将增加我们对不同类别的重塑机制如何控制不同生物学过程的理解。