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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：
7525918
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/7525918
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 Condition DNA DNA Damage DNA Double Strand Break DNA Repair DNA lesion Defect Detection Disruption Eukaryota Eukaryotic Cell 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 Modeling Modification Molecular Molecular Genetics Mutagens Mutation Nuclear Nuclear Protein Nuclear Proteins Null Lymphocytes Play Process Proteins Public Health Radiation Relaxation Role Saccharomycetales Signal Transduction System UV induced Work Yeast Model System base cancer therapy chromatin remodeling design loss of function member novel novel therapeutics repaired response therapeutic target 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（由申请人提供）：Ino80染色质重塑复合物在低等真核生物中辐射诱导的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，证明在高度紧凑的染色质结构中 DNA 的可及性是 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取决于 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作用。虽然前两种机制在过去几十年中一直是广泛研究的主题，但染色质修饰和重塑在 DNA 损伤反应中的作用仍然很大程度上不清楚，特别是在哺乳动物系统中。我们提出的研究旨在阐明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。我们的重点将放在 Ino80 ATP 依赖性染色质重塑复合物的两个关键亚基上，即 Ino80 和 Arp5。 Ino80 是 SNF2 超家族的独特成员，被认为是协助 DNA 修复的特殊染色质重塑剂。 Arp5 是一种肌动蛋白相关核蛋白，也是 Ino80 复合物的一个完整亚基。芽殖酵母中任一基因的突变都会使细胞对多种基因毒性剂过敏。在此应用中，我们试图了解 Ino80 如何调节 DNA 损伤反应。我们已经通过同源靶向成功创建了 INO80 和 ARP5 功能丧失的人类细胞模型。这些遗传模型系统将作为独特的工具来研究 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的功能。我们的结果有望进一步阐明 DNA 损伤反应系统的机制和整个基因组不稳定性的分子基础。我们的结果也应该有助于识别新的治疗靶点，特别是放射增敏靶点。公共卫生相关性：接触 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旨在通过使用分子和遗传学方法来了解染色质重塑复合物在创建此类通路中的作用。拟议工作的结果有可能揭示遗传不稳定性的新机制并确定癌症治疗的新靶点。