Nuclear receptor coactivator PGC-1a in DNA damage

DNA损伤中的核受体共激活剂PGC-1a

• 批准号: 7019236
• 负责人: Anastasia Kralli
• 金额: $ 18.59万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019236
• 关键词: DNA damage; DNA repair; acyltransferase; apoptosis; cell line; chromatin immunoprecipitation; gamma radiation; gene deletion mutation; gene induction /repression; genetic regulation; genetic transcription; immunofluorescence technique; immunoprecipitation; nuclear receptors; protein localization; protein protein interaction; protein structure function; transcription factor

In response to DMA damage, cells induce the expression of gene programs that facilitate the repair of the damaged DMA, ensure cell cycle arrest until the damage is repaired, and can, depending on the extent of damage, lead to cell death via apoptosis. The transcriptional induction of the program is vital for promoting the survival of cells with integral genomes, while eliminating cells with defects that can lead to genomic instability and cancer. The DMA damage response pathway is linked to the metabolic state of organisms, via not yet well understood pathways. Our long term goal is to understand the regulatory networks that integrate information from the metabolic state of an organism to specific transcriptional responses in the nucleus. As a step towards this goal, we will study the role of the nuclear receptor coactivator PGC-1a, which senses changes in the metabolic state of organisms, in the gene expression programs of the cellular response to DMA damage. The proposed work will test the hypothesis that PGC-1a regulates the response to DNA damage, and address the mechanism that enables PGC-1a to act in this pathway. To test the hypothesis, we will i) compare the DNA damage response in cells that express and do not express PGC-1a, and ii) define the role of Tip60 and nuclear receptors in mediating the function of PGC-1a. Our studies will provide insights into the mechanisms that link metabolism and efficiency of DNA damage responses, and into yet uncharacterized functions of PGC-1a and Tip60. Elucidation of such mechanisms is important for devising strategies that counteract the harmful effects of metabolic disease on DNA repair and cell survival. Relevance to public health. The mechanisms that communicate information from the metabolic state of an organism (e.g. body mass index, blood glucose levels, diet, physical exercise, metabolic disease, hormonal profile) to the cellular machinery that coordinates the repair of damage to DNA and the survival of healthy cells with intact genomes are not known. Defects in such repair can lead to the uncontrollable proliferation of cells with unstable genomes and predisposion to cancer, or aberrant cell death and degenerative diseases. Understanding the ways by which the metabolic state communicates to the cellular DNA damage response pathway is important for devising strategies that counteract the damage imposed by metabolic disease.

为了响应 DMA 损伤，细胞诱导基因程序的表达，促进受损 DMA 的修复，确保细胞周期停滞直至损伤修复，并且根据损伤程度，可以通过细胞凋亡导致细胞死亡。该程序的转录诱导对于促进具有完整基因组的细胞的存活至关重要，同时消除具有可能导致基因组不稳定和癌症的缺陷的细胞。 DMA 损伤反应途径通过尚未充分了解的途径与生物体的代谢状态相关。我们的长期目标是了解将生物体代谢状态的信息整合到细胞核中特定转录反应的调控网络。作为一个 为了实现这一目标，我们将研究核受体共激活剂 PGC-1a 在细胞对 DMA 损伤反应的基因表达程序中的作用，PGC-1a 感知生物体代谢状态的变化。拟议的工作将测试 PGC-1a 调节对 DNA 损伤的反应的假设，并探讨使 PGC-1a 在此途径中发挥作用的机制。为了检验这一假设，我们将 i) 比较表达和不表达 PGC-1a 的细胞中的 DNA 损伤反应，以及 ii) 定义 Tip60 和核受体在介导 PGC-1a 功能中的作用。我们的研究将深入了解连接新陈代谢和 DNA 损伤反应效率的机制，以及 PGC-1a 和 Tip60 尚未表征的功能。阐明此类机制对于设计非常重要 抵消代谢疾病对 DNA 修复和细胞存活的有害影响的策略。与公共卫生的相关性。将生物体代谢状态（例如体重指数、血糖水平、饮食、体育锻炼、代谢疾病、荷尔蒙概况）信息传达给协调 DNA 损伤修复和健康生存的细胞机制的机制具有完整基因组的细胞尚不清楚。这种修复的缺陷可能导致基因组不稳定的细胞不受控制地增殖，并容易患癌症、异常细胞死亡和退行性疾病。了解代谢状态与细胞 DNA 损伤反应的沟通方式 途径对于制定对抗代谢疾病造成的损害的策略非常重要。