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

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% ofku80 ^−/− p53 ^+/− mice developed a broad spectrum of cancer by 40 weeks and allku80 ^−/− 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 G₁/S checkpoint due to the p53 mutation and are hypersensitive to γ-radiation and reactive oxygen species due to the Ku80mutation. These data show that replicative senescence is caused by a p53-dependent cell cycle response to damaged DNA inku80 ^−/− cells and that p53 is essential for preventing very early onset of pro-B-cell lymphoma inku80 ^−/− mice.