Nuclear receptor coactivator PGC-1a in DNA damage

响应于DMA损伤，细胞诱导基因程序的表达，所述基因程序促进损伤的DMA的修复，确保细胞周期停滞直到损伤被修复，并且可以根据损伤的程度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损伤反应途径与生物体的代谢状态有关，通过尚未完全理解的途径。我们的长期目标是了解整合生物体代谢状态信息到细胞核中特定转录反应的调控网络。作为 为了实现这一目标，我们将研究核受体辅激活剂PGC-1a在细胞对DMA损伤反应的基因表达程序中的作用，PGC-1a可感知生物体代谢状态的变化。这项工作将验证PGC-1a调节DNA损伤反应的假设，并解决PGC-1a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，和ii）确定Tip 60和核受体在介导PGC-1a功能中的作用。我们的研究将提供深入了解的机制，链接代谢和DNA损伤反应的效率，并到尚未表征的功能PGC-1a和Tip 60。阐明这种机制对于设计 对抗代谢疾病对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。将生物体的代谢状态（例如体重指数、血糖水平、饮食、体育锻炼、代谢疾病、激素谱）的信息传递到协调DNA损伤的修复和具有完整基因组的健康细胞的存活的细胞机制的机制尚不清楚。这种修复的缺陷可能导致基因组不稳定的细胞无法控制的增殖，并易患癌症，或异常细胞死亡和退行性疾病。了解代谢状态与细胞DNA损伤反应的联系方式 代谢途径对于设计对抗代谢疾病造成的损害的策略非常重要。

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.