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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：
8318991
负责人：
LEI LI
金额：
$ 25.82万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318991
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 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 repaired response tool

项目摘要

ABSTRACT 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. NARRATIVE 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.

摘要