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: 8065754
• 负责人: Tej K Pandita
• 金额: $ 32.89万
• 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/8065754
• 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; DNA-PKcs; 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; 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; TP53 gene; 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; public health relevance; 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损伤激活了信号转导途径，这些途径迅速影响下游过程，例如基因转录，细胞周期进展和DNA复制。所有这些过程都需要染色质改变以允许DNA访问。几年来，我们一直在研究ATM（在共济失调 - 凝血症中突变）在端粒染色质结构的DNA损伤修复和维持中的作用。缺乏ATM的细胞在DNA修复中存在缺陷，并显示出改变的端粒染色质结构。最近，我们已经确定了一种染色质修改因子“ HMOF”果蝇基因的人类直系同源物（第一个雄性）对于小鼠早期胚胎生存至关重要。 HMOF具有与ATM相互作用的染色体和组蛋白乙酰转移酶（HAT）活性。细胞接触IR可增强其靶标底物（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的失活导致ATM自磷酸化，ATM激酶活性和DNA修复的废除，同时增加IR暴露后的细胞杀伤。基于这些初步研究，HMOF参与了ATM的IR依赖性激活，我们假设HMOF除了参与调节DNA损伤引起的ATM激活外，还具有多个角色。在拟议的工作中，我们将确定HMOF在IR反应中的独立ATM独立作用，用于细胞存活，DNA DSB修复和端粒代谢。该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反应中的独立作用的理解。最终，了解HMOF和ATM之间的联系可能会提供改变对IR的反应的策略，因为肿瘤细胞和正常细胞在其染色质结构和端粒代谢方面存在显着差异。公共卫生相关性：该项目将定义HMOF在电离辐射，端粒代谢和DNA修复的细胞反应中的作用。拟议研究的结果将进一步了解HMOF如何参与识别，信号和修复双链断裂。此外，这项研究将为了解DNA访问的染色质屏障如何受HMOF活性的调节，以确保DNA DSB的端粒维持和修复。因此，理解这些机制对于预防癌症以及针对疾病疾病 - texia- telangictia优化靶向和组合治疗方案的策略至关重要。