Genomic instability is a major cause of cancer and believed to be a major contributor to aging. The gene Xrcc5, that codes for the protein, Ku80 is important for maintaining genomic stability by repairing double-strand breaks (DSBs) in DNA and by capping chromosomal ends. Mice deleted for Ku80 are immunodeficient due to defective repair of DSBs that occur during Variable (Diversity) Joining recombination and cells derived from ku80-mutant mice are hypersensitive to ionizing radiation and reactive oxygen species. In addition, these cells exhibit cytogenetic aberrations including telomeric fusions. ku80-mutant mice exhibit an early onset of age-related changes in a variety of tissues that are also observed in control mice; thus, Ku80 may be important for the normal aging process. These changes include growth plate closure, osteopenia, skin and follicular atrophy, degenerative processes in the liver and shortened life span. Early mortality was at least partly due to early onset of the age - specific diseases, sepsis and cancer. Even though onset of cancer is early for ku80-mutant mice, the total incidence is low. Interestingly, deletion of the tumor suppressor protein, p53, greatly increased the risk of lymphoma suggesting that Ku80 is also a tumor suppressor. The biological role of Ku80 in maintaining genomic stability will be determined during aging and oncogenesis and completion of this proposal will significantly impact our understanding of Ku80's role during these events. l: Determine the contribution genomic instability, induced by either oxidative damage or telomere dysfunction, has on the ku80-mutant phenotype. The onset and spectra of genetic mutations will be compared between ku80-mutant and control mice. To determine the impact of oxidative damage, DNA lesions will be measured in ku80- mutant mice after exposure to ionizing radiation and by overexpressing proteins that eliminate oxygen radicals, catalase and Cu/Zn-superoxide dismutase. To investigate the impact of telomere maintenance, ku80-/- mTR-/- mice will be investigated. 2: Determine the impact general genomic instability has on oncogenesis in ku80-mutant mice that are deleted for p53 in nonlymphoid tissue. The role of the tumor suppression protein, p53, will be analyzed for its impact on oncogenesis in ku80-mutant mice with specific attention given to mammary tissue in a defined mouse model.