Analysis of ku80-mutant mice and cells with deficient levels of p53.
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 gamma-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.
Lim
D S
DS
Lexicon Genetics, The Woodlands, Texas 77381-4287, USA.
Vogel
H
H
Willerford
D M
DM
Sands
A T
AT
Platt
K A
KA
Hasty
P
P
D000375:Aging / Q000502:physiology*; D000818:Animals; D034961:Antigens, Nuclear; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015994:Incidence; D000072200:Ku Autoantigen; D016393:Lymphoma, B-Cell / Q000453:epidemiology*; D051379:Mice; D018345:Mice, Knockout; D009152:Mutagenicity Tests; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013308:Streptonigrin / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D013308:Streptonigrin; D006861:Hydrogen Peroxide; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen