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 G1/S checkpoint due to the p53 mutation and are hypersensitive to χ-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.
Original language | English (US) |
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Pages (from-to) | 3772-3780 |
Number of pages | 9 |
Journal | Molecular and cellular biology |
Volume | 20 |
Issue number | 11 |
DOIs | |
State | Published - Jun 2000 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology