Nuclear receptor coactivator PGC-1a in DNA damage

作为对DMA损伤的反应，细胞诱导促进DNA损伤修复的基因程序的表达，确保细胞周期停止，直到损伤被修复，并可根据损伤的程度，通过凋亡导致细胞死亡。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，同时消除可能导致基因组不稳定和癌症的缺陷细胞。DMA损伤反应途径与生物体的新陈代谢状态有关，其途径尚未被很好地理解。我们的长期目标是了解调控网络，该网络将生物体代谢状态的信息整合到细胞核中的特定转录反应中。作为一名 为了实现这一目标，我们将研究核受体辅活化子PGC-1a在细胞对DMA损伤反应的基因表达程序中的作用。PGC-1a可以感知生物体代谢状态的变化。这项拟议的工作将检验PGC-1a调节DNA损伤反应的假设，并解决使PGC-1a能够在这一途径中发挥作用的机制。为了验证这一假设，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)确定Tip60和核受体在介导PGC-1a功能中的作用。我们的研究将为我们深入了解DNA损伤反应的代谢和效率的机制，以及PGC-1a和Tip60尚未确定的功能。对这种机制的阐明对于设计 对抗代谢性疾病对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。从生物体的代谢状态(如体重指数、血糖水平、饮食、体育锻炼、代谢性疾病、激素谱)到协调DNA损伤修复和拥有完整基因组的健康细胞生存的细胞机制的机制尚不清楚。这种修复的缺陷可能会导致基因组不稳定的细胞无法控制地增殖，并易患癌症，或者细胞异常死亡和退行性疾病。了解代谢状态与细胞DNA损伤反应的联系方式 通路对于设计对抗代谢性疾病造成的损害的策略很重要。

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.