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.
