Analysis of ku80-mutant mice and cells with deficient levels of p53

Absence of Ku80 results in increased sensitivity to ionizing radiation, def ective lymphocyte development, early onset of an age-related phenotype, and premature replicative senescence. Here we investigate the role of p53 on t he phenotype of ku80-mutant mice and cells. Reducing levels,of p53 increase d the cancer incidence for ku80(-/-) mice. About 20% of ku80(-/-) p53(+/-) mice developed a broad spectrum of cancer by 40 weeks and all ku80(-/-) p53 (-/-) mice developed pro-B-cell lymphoma by 16 weeks. Reducing levels of p5 3 rescued populations of ku80(-/-) cells from replicative senescence by ena bling spontaneous immortalization. The double-mutant cells are impaired for the G(1)/S checkpoint due to the p53 mutation and are hypersensitive to ga mma-radiation and reactive oxygen species due to the Ku80 mutation. These d ata show that replicative senescence is caused by a p53-dependent cell cycl e response to damaged DNA in ku80(-/-) cells and that p53 is essential for preventing very early onset of pro-B-cell lymphoma in ku80(-/-) mice.