Analysis of ku80 -Mutant Mice and Cells with Deficient Levels of p53

Abstract

ABSTRACT Absence of Ku80 results in increased sensitivity to ionizing radiation, defective lymphocyte development, early onset of an age-related phenotype, and premature replicative senescence. Here we investigate the role of p53 on the phenotype of ku80 -mutant mice and cells. Reducing levels of p53 increased 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 p53 rescued populations of ku80 −/− cells from replicative senescence by enabling spontaneous immortalization. The double-mutant cells are impaired for the G 1 /S checkpoint due to the p53 mutation and are hypersensitive to γ-radiation and reactive oxygen species due to the Ku80 mutation. These data show that replicative senescence is caused by a p53-dependent cell cycle 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.