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ATP-Dependent Chromatin Remodeling and Genomic Instability in Mammalian Cells

哺乳动物细胞中 ATP 依赖性染色质重塑和基因组不稳定性

基本信息

批准号：
7849035
负责人：
LEI LI
金额：
$ 28.76万
依托单位：
UNIVERSITY OF TX MD ANDERSON 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 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849035
关键词：
Actins Address Affect Alleles Amino Acid Motifs Apoptosis Apoptotic Biological Models Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Regulation Cell Proliferation Cell model Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA lesion Defect Detection Eukaryota Excision Genes Genetic Genetic Models Genetic Recombination Genetic Transcription Genome Stability Genomic Instability Genomics Goals Histones Human Human Genome Investigation Ionizing radiation Lead Lesion Maintenance Mammalian Cell Mammalian Genetics Molecular Molecular Genetics Mutagens Mutation Nuclear Nuclear Protein Nuclear Proteins Null Lymphocytes Play Process Proteins Radiation Relaxation Role Saccharomycetales Signal Transduction System UV induced Work Yeast Model System base cancer therapy chromatin modification chromatin remodeling design loss of function member new therapeutic target novel protein complex public health relevance repaired response tool

项目摘要

DESCRIPTION (provided by applicant): The Ino80 chromatin remodeling complex plays an important role in the repair of radiation-induced DNA double strand breaks in lower eukaryotes. This discovery provides the first strong evidence that accessibility to DNA in the context of highly compact chromatin structure is a critical factor in DNA damage response. It becomes increasingly clear that maintenance of genome stability depends on highly coordinated actions of DNA damage repair, cell cycle checkpoint, and chromatin remodeling mechanisms. While the first two mechanisms have been the subject of extensive investigations during the past decades, the role of chromatin modification and remodeling in DNA damage response remains largely unclear, particularly in mammalian systems. Our proposed studies are aimed at delineating how chromatin remodeling activities support removal of DNA lesions and initiation of damage-induced cell cycle checkpoint signals. Our focus will be on two key subunits of the Ino80 ATP-dependent chromatin remodeling complex, Ino80 and Arp5. Ino80 is a unique member of the SNF2 superfamily that is believed to be a specialized chromatin remodeler assisting in DNA repair. Arp5 is an actin-related nuclear protein and an integral subunit of the Ino80 complex. Mutations of either gene in budding yeast render cells hypersensitive to a broad spectrum of genotoxic agents. In this application, we seek to understand how Ino80 modulates DNA damage responses. We have successfully created, via homologous targeting, loss-of-function human cellular models for INO80 and ARP5. These genetic model systems will serve as unique tools to study the function of Ino80 and Arp5 in cell proliferation, repair of ionizing radiation and UV-induced DNA lesions, damage-induced cell cycle arrest, and apoptosis. Our results are expected to further elucidate the mechanisms of the DNA damage response system and the molecular basis of genomic instability at large. Our results should also be useful for identification of novel therapeutic targets, especially targets for radiation sensitization. PUBLIC HEALTH RELEVANCE: Access to DNA lesions is a key prerequisite for many cellular mechanisms that act to protect the integrity of the human genome. Studies proposed in this application seek to understand the role of chromatin remodeling complex in creating such access by using molecular and genetics approaches. Results from the proposed work have the potential to unveil novel mechanism of genetic instability and to identify novel targets for cancer therapy.

描述(申请人提供)：INO80染色质重塑复合体在低等真核生物辐射诱导的DNA双链断裂的修复中发挥重要作用。这一发现提供了第一个强有力的证据，证明在高度紧密的染色质结构背景下接触DNA是DNA损伤反应的关键因素。越来越清楚的是，基因组稳定性的维持依赖于DNA损伤修复、细胞周期检查点和染色质重塑机制的高度协调行动。尽管前两种机制在过去几十年中得到了广泛的研究，但染色质修饰和重塑在DNA损伤反应中的作用仍然很不清楚，特别是在哺乳动物系统中。我们拟议的研究旨在描绘染色质重塑活动如何支持DNA损伤的去除和损伤诱导的细胞周期检查点信号的启动。我们的重点将是INO80依赖于ATP的染色质重塑复合体的两个关键亚单位，INO80和Arp5。INO80是SNF2超家族中一个独特的成员，被认为是一种专门的染色质重构体，有助于DNA修复。Arp5是一种肌动蛋白相关的核蛋白，是INO80复合体的一个完整亚基。萌芽酵母中的任何一个基因的突变都会使细胞对广泛的遗传毒物过敏。在这个应用中，我们试图了解INO80是如何调节DNA损伤反应的。通过同源靶向，我们已经成功地为INO80和ARP5建立了功能丧失的人类细胞模型。这些遗传模型系统将成为研究INO80和Arp5在细胞增殖、电离辐射和紫外线诱导的DNA损伤修复、损伤诱导的细胞周期停滞和细胞凋亡中作用的独特工具。我们的结果有望进一步阐明DNA损伤反应系统的机制和基因组不稳定的分子基础。我们的结果也应该有助于识别新的治疗靶点，特别是辐射增敏的靶点。公共卫生相关性：获得DNA损伤是许多保护人类基因组完整性的细胞机制的关键先决条件。本申请中提出的研究试图通过分子和遗传学方法了解染色质重塑复合体在创建这种通道中的作用。这项拟议工作的结果有可能揭示遗传不稳定的新机制，并确定癌症治疗的新靶点。