Ku80 in genomic stability and DNA damage responses

The ku80-/- phenotype reflects premature aging and defective repair for both nonspecific (genomic instability) and Rag-specific DSBs (immunodeficiency). ku80-/- mice also exhibit neuronal apoptosis, it is unclear the type of DSB responsible for this response. In spite of genomic instability and immunodeficiency, cancer incidence is not increased in ku80-/- mice. However, deletion of the tumor suppressor p53 greatly increases pro-B cell lymphatic in ku80-/- mice due to IgH/c-Myc translocations suggesting responses to Rag-specific DSBs suppress cancer. Here I delete Rag-1 from ku80-/- p53-/- mice to differentiate the impact nonspecific vs. Rag-specific DSBs have on ku80-/- mice. I find deleting Rag-1 prevents pro-B cell lymphatic confirming Rag-induced DSBs induce this form of cancer. Both the triple mutant mice and the p53-/- rag-1-/- mice exhibit T-cell lymphatic and medulloblastoma. Thus, p53-mediated neuronal apoptosis likely suppresses medulloblastoma in ku80-deleted mice and Ku80 likely suppresses medulloblastoma by repairing nonspecific DSBs.; I show removing Ku80 from mice with dysfunctional DNA responses exacerbates oncogenesis and deleting Ku80 ameliorates the tumor burden in mice with functional p53-reponses. The APCMIN mutation was crossed into the ku80-/- mice. APC is a tumor suppressor gene and heterozygous mice are predisposed to adenomas along the small intestine. If responses to DNA damage are accountable for low cancer incidence in ku80-/- mice, then deletion of Ku80 should decrease the tumor burden and increase life span of APCMIN mice. Deletion of Ku80 extends the lifespan of APCMIN mice and reduces tumor number, suggesting either delayed onset or progression or reduced formation of cancer in ku80-/- APCMIN mice. Moreover, mutation analysis of the intestine shows an increase in gross chromosomal rearrangements supporting the idea that inefficient repair of DNA damage is likely contributing to heightened cellular responses.; Additionally, it is unclear whether nonspecific or Rag-specific DSBs cause ku80-/- mouse premature aging. Here I delete Rag-1 to cause scid in both control and ku80-/- mice and show loss of Ku80 is associated with a number of aging-related characteristics independently of Rag-1 status suggesting defective repair of nonspecific damage is the root basis of premature aging. Furthermore, rag-1-/- mice do not exhibit an early aging phenotype showing that stress responses associated with SCID do not exacerbate aging.