CHROMATIN MODIFYING FACTORS CONTROL RADIATION RESPONSE AND GENOMIC STABILITY

染色质修饰因子控制辐射反应和基因组稳定性

• 批准号: 8109975
• 负责人: Tej K Pandita
• 金额: $ 31.99万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109975
• 关键词: ATM activation; ATM function; Acetylation; Affect; Appearance; Ataxia Telangiectasia; Ataxia-Telangiectasia-Mutated protein kinase; Biochemical; Biological Assay; Cell Cycle; Cell Cycle Progression; Cell Survival; Cells; Chromatin; Chromatin Structure; Chromosome abnormality; Chromosomes; Clinical; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA biosynthesis; Defect; Development; Disease; Dominant-Negative Mutation; Double Strand Break Repair; Drosophila genus; Ectopic Expression; Embryo; Ensure; Eukaryotic Cell; Exposure to; Functional disorder; Genes; Genetic Transcription; Genome Stability; Genomic Instability; Goals; Health; Histone Acetylation; Histone H4; Histones; Human; Immunoprecipitation; Ionizing radiation; Kinetics; Link; Lysine; Measures; Mediator of activation protein; Metabolism; Metaphase; Mus; Mutate; NBS1 gene; Nonhomologous DNA End Joining; Normal Cell; Nuclear Matrix; Orthologous Gene; Periodicity; Phase; Phosphorylation; Point Mutation; Principal Investigator; Process; Radiation; Radiation Induced DNA Damage; Radiation therapy; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Telomere Maintenance; Telomere-Binding Proteins; Testing; Transferase; Treatment Protocols; Work; base; cancer prevention; cell killing; combinatorial; histone acetyltransferase; histone modification; homologous recombination; improved; male; neoplastic cell; programs; repaired; research study; response; telomerase reverse transcriptase; telomere

DESCRIPTION (provided by applicant): In eukaryotic cells, ionizing radiation (IR) induced DNA damage activates signal transduction pathways that rapidly affect downstream processes such as gene transcription, cell-cycle progression and DNA replication. All of these processes require chromatin alterations to allow for DNA access. For several years we have been studying the role of the ATM (mutated in ataxia-telangiectasia) in DNA damage repair and maintenance of telomere chromatin structure. Cells deficient in ATM have defects in DNA repair and display altered telomere chromatin structure. Recently, we have identified a chromatin-modifying factor "hMOF" the human ortholog of Drosophila MOF gene (males absent on the first) that is essential for early embryonic survival in mice. hMOF has a chromodomain and histone acetyltransferase (HAT) activity that interacts with ATM. Cellular exposure to IR enhances hMOF-dependent acetylation of its target substrate, lysine 16 (K16) of histone H4, independent of ATM function. However, inactivation of hMOF results in abrogation of ATM autophosphorylation, ATM kinase activity and DNA repair while increasing cell killing after IR exposure. Based on these preliminary studies, that hMOF participates in the IR-dependent activation of ATM, we hypothesize that hMOF has multiple roles in addition to being involved in the regulation of DNA damage-induced ATM activation. In the proposed work, we will determine ATM independent role of hMOF in IR response for cell survival, DNA DSB repair and telomere metabolism. Experiments described in this proposal will investigate the functional links between hMOF and IR response. We will investigate mechanisms by which hMOF influences genomic instability. These studies will improve our understanding of the role of hMOF in telomere chromatin structure, DNA DSB repair and, ATM independent role of the MOF in IR response. Ultimately, understanding the links between hMOF and ATM could provide strategies for modifying the response to IR that could be useful in clinical radiation therapy, since tumor cells and normal cells have significant differences in their chromatin structure and telomere metabolism. PUBLIC HEALTH RELEVANCE: This project will define the role of hMOF in the cellular response to ionizing radiation, telomere metabolism and DNA repair. The results of the proposed studies will further our understanding of how hMOF is involved in recognizing, signaling and repairing double-strand breaks. In addition this study will provide the mechanistic basis for understanding how the chromatin barrier to DNA access is regulated by hMOF activity to ensure telomere maintenance and repair of DNA DSBs. Thus understanding these mechanisms is critical to both cancer prevention as well as development of strategies to optimize targeted and combinatorial treatment regimens with regard to the disease Ataxia- Telangiectasia.

描述（由申请人提供）：在真核细胞中，电离辐射（IR）诱导的 DNA 损伤激活信号转导途径，迅速影响下游过程，如基因转录、细胞周期进程和 DNA 复制。所有这些过程都需要染色质改变以允许 DNA 进入。多年来，我们一直在研究 ATM（共济失调毛细血管扩张症突变）在 DNA 损伤修复和端粒染色质结构维持中的作用。缺乏 ATM 的细胞在 DNA 修复方面存在缺陷，并显示端粒染色质结构发生改变。最近，我们发现了一种染色质修饰因子“hMOF”，它是果蝇 MOF 基因的人类直系同源物（雄性在第一个基因中缺失），它对于小鼠早期胚胎的存活至关重要。 hMOF 具有与 ATM 相互作用的染色质结构域和组蛋白乙酰转移酶 (HAT) 活性。细胞暴露于 IR 会增强其靶底物、组蛋白 H4 的赖氨酸 16 (K16) 的 hMOF 依赖性乙酰化，与 ATM 功能无关。然而，hMOF 失活会导致 ATM 自磷酸化、ATM 激酶活性和 DNA 修复消失，同时增加红外线照射后的细胞杀伤力。基于这些初步研究，hMOF 参与了 IR 依赖性的 ATM 激活，我们假设 hMOF 除了参与调节 DNA 损伤诱导的 ATM 激活之外，还具有多种作用。在拟议的工作中，我们将确定 hMOF 在细胞存活、DNA DSB 修复和端粒代谢的 IR 响应中的 ATM 独立作用。本提案中描述的实验将研究 hMOF 和 IR 响应之间的功能联系。我们将研究 hMOF 影响基因组不稳定性的机制。这些研究将提高我们对 hMOF 在端粒染色质结构、DNA DSB 修复以及 MOF 在 IR 响应中的 ATM 独立作用的理解。最终，了解 hMOF 和 ATM 之间的联系可以提供改变对 IR 反应的策略，这可能在临床放射治疗中有用，因为肿瘤细胞和正常细胞在染色质结构和端粒代谢方面存在显着差异。公共健康相关性：该项目将定义 hMOF 在细胞对电离辐射、端粒代谢和 DNA 修复的反应中的作用。拟议研究的结果将进一步加深我们对 hMOF 如何参与识别、发出信号和修复双链断裂的理解。此外，这项研究将为理解 hMOF 活性如何调节 DNA 进入的染色质屏障提供机制基础，以确保 DNA DSB 的端粒维持和修复。因此，了解这些机制对于癌症预防以及制定优化针对共济失调-毛细血管扩张症的靶向和组合治疗方案的策略至关重要。