6. Project Summary/Abstract SIRTUIN (SIRT) genes modulate aging and lifespan in multiple organisms, through regulation of genomic stability, stress-resistance, and metabolism. In mammals, the SIRTUIN gene SIRT7 has multiple links to aging and age-related disease. SIRT7 is implicated in cell death, stress resistance, and inflammation in cardiac tissue, and SIRT7 mutant mice suffer from inflammatory and degenerative cardiac disease. SIRT7 is on a chromosomal region that is frequently mutated acute leukemia, lymphoma, and other aging-associated cancers, and SIRT7 protein levels are increased in tumor tissues. Thus, SIRT7 is linked to multiple physiologic and disease processes that directly impact on the health of the veterans. Despite these important links of SIRT7 to human disease processes, relatively little is understood about its molecular mechanisms of action. The research proposed here aims to elucidate SIRT7 mechanisms. The work will investigate the hypothesis that SIRT7 exerts effects on aging- and cancer- associated cellular programs through a novel biochemical activity at chromatin, the molecular structure in which the DNA of mammalian genomes is packaged. The long- term goals of the research are to elucidate the molecular pathways through which chromatin regulation by SIRT7 influences cancer, metabolism, and other age-related pathologies, and identify cellular programs that can be targeted for therapeutic intervention. With the growing numbers of aging veterans, these studies should be highly relevant for biomedical advancements to benefit veterans' health. Specific Aim I: To elucidate the role of SIRT7 in genome stabilization and DNA damage responses. Environmental and metabolic sources of DNA damage and genotoxic stress contribute to genomic instability, aging, and age-related tissue degeneration and pathologies. Preliminary data suggest that SIRT7 influences cellular responses to genotoxic stress through a novel enzymatic activity at chromatin. Biochemical, cell biological, and cytogenetic approaches will be used to define the role and mechanisms of action of SIRT7 in genome stabilization, DNA damage signaling, and DNA repair. Specific Aim II: To elucidate the function of SIRT7 in cellular senescence. Cellular senescence programs are triggered by telomere dysfunction, DNA damage, activated oncogenes, and other cellular stresses in the contexts of cancer and aging. In preliminary work, SIRT7 inactivation leads to premature senescence. Functional and biochemical studies will be carried out to determine the molecular mechanisms and physiologic contexts of SIRT7 function in cellular senescence. Specific Aim III: To identify and characterize the function of SIRT7 in gene expression networks and nuclear signaling pathways in epigenetic aging-associated cellular programs. Establishment of specialized chromatin states plays important roles in epigenetic regulation of cellular gene expression programs that impact on molecular pathways in aging and cancer. Candidate quantitative gene expression analysis coupled with pathway-specific array approaches will be used to identify gene targets of SIRT7-dependent chromatin regulation. Focus will be placed on epigenetic gene expression programs associated with DNA damage responses, cellular senescence, and cellular transformation.