Basis for Distinct Functions of ATP-Dependent Chromatin Remodeling Complexes

ATP 依赖性染色质重塑复合物的独特功能的基础

基本信息

批准号：
7650134
负责人：
HUA-YING FAN
金额：
$ 33.16万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7650134
关键词：
ATP Hydrolysis Age Apoptosis B-Lymphocytes Binding Binding Proteins Biochemical Biological Assay Biological Process Cell Line Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Cockayne Syndrome Complex DNA DNA Binding DNA Repair DNA lesion Defect Development Disease Event Genetic Transcription Goals Hela Cells Histones Human In Vitro Induction of Apoptosis Lead Learning MDM2 gene Malignant Neoplasms Mass Spectrum Analysis Mediating Memory Missense Mutation Modeling Molecular Conformation Mutation Nuclear Nucleosomes Null Lymphocytes Patients Phenocopy Play Positioning Attribute Process Protein Isoforms Proteins Public Health Recombinants Recruitment Activity Research Project Grants Role SMARCA4 gene Small Interfering RNA Structure TP53 gene Tail Techniques Type II Cockayne Syndrome UV induced UV sensitive Ultraviolet Rays base cellular engineering chromatin remodeling histone modification human TYRP1 protein human disease in vivo insight malignant breast neoplasm mutant nervous system disorder novel p53-binding protein repaired research study

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand how ATP-dependent chromatin remodelers influence diverse biological processes. The experiments outlined here focus on understanding how the CSB (Cockayne Syndrome complementation group B) chromatin remodeler modulates chromatin structure and how defects in this protein lead to disease. ATPdependent chromatin remodelers alter chromatin structure non-covalently to regulate DNA access and/or space nucleosomes. Thus, these activities play important roles in regulating nuclear processes such as transcription, replication and DNA repair as well as developmental events including transcriptional memory and cell-fate determination. Mutations in CSB lead to Cockayne syndrome: a disease in which patients are highly sensitive to UV light, age prematurely, and suffer from profound developmental and neurological disorders. CSB plays a pivotal role in transcription-coupled DNA repair; however, little is known as to how its remodeling activity influences this process. The availability of mutant CSB cell lines that phenocopy some of the defects associated with Cockayne syndrome (such as UV sensitivity) makes CSB an excellent candidate remodeler to elucidate the relationship between the biochemical activities and biological functions of ATPdependent chromatin remodeling complexes. To obtain greater insight into the mechanism whereby CSB remodels chromatin, and to elucidate the contribution of this activity to normal development, DNA repair and disease, we propose three aims (1) Dissect the mechanism of CSB remodeling activity, (2) Dissect the functions of CSB in transcription-coupled DNA repair, and (3) Investigate the impact of CSB-binding proteins on CSB function. PUBLIC HEALTH REVELANCE: Chromatin is the fundamental template for all nuclear process and there are countless examples of human disease resulting from misregulation of chromatin structure, including cancer. This proposed research project will not only reveal the underlying mechanism that directly lead to the devastating disease Cockayne syndrome, but offer important insights into the fundamental principles that regulate chromatin structure.

描述（由申请人提供）：该提案的总体目标是了解ATP依赖性染色质改造如何影响多种生物学过程。此处概述的实验专注于了解CSB（Cockayne综合征补充b）染色质改建器调节染色质结构以及该蛋白质中的缺陷如何导致疾病。依赖ATP的染色质重塑剂非共价改变染色质结构，以调节DNA访问和/或空间核小体。因此，这些活动在调节核过程中起着重要作用，例如转录，复制和DNA修复以及包括转录记忆和细胞命令测定在内的发展事件。 CSB的突变导致Cockayne综合征：患者对紫外线高度敏感，年龄过早，并且患有深远的发育和神经系统疾病。 CSB在转录耦合的DNA修复中起关键作用；但是，关于其重塑活动如何影响这一过程的重塑活动鲜为人知。表观复制的突变CSB细胞系的可用性与Cockayne综合征相关的某些缺陷（例如紫外线敏感性）使CSB成为阐明ATP依赖性染色质重塑复合物的生化活性与生物学功能之间关系的极好的候选重塑剂。为了更深入地了解CSB重塑染色质的机制，并阐明了该活动对正常发育，DNA修复和疾病的贡献，我们提出了三个目标（1）解剖CSB重塑活性的机制，（（2）剖析CSB在转录连接的DNA修复中的功能，并（3）调查了css conteb of cossb的功能。公共卫生的启示：染色质是所有核过程的基本模板，并且有无数的人类疾病的例子，这是由于染色质结构（包括癌症）的不良调节而导致的。该提出的研究项目不仅将揭示直接导致灾难性疾病Cockayne综合征的潜在机制，而且还提供了对调节染色质结构的基本原理的重要见解。