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

Mol Cell Biol. 2000 Jun;20(11):3772-80. doi: 10.1128/MCB.20.11.3772-3780.2000.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / physiology*
  • Animals
  • Antigens, Nuclear*
  • Cell Cycle / drug effects
  • Cell Division
  • Cells, Cultured
  • DNA Damage / drug effects
  • DNA Helicases*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Hydrogen Peroxide / pharmacology
  • Incidence
  • Ku Autoantigen
  • Lymphoma, B-Cell / epidemiology*
  • Mice
  • Mice, Knockout
  • Mutagenicity Tests
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Signal Transduction / drug effects
  • Streptonigrin / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antigens, Nuclear
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • Streptonigrin
  • Hydrogen Peroxide
  • DNA Helicases
  • XRCC5 protein, human
  • Xrcc6 protein, human
  • Xrcc6 protein, mouse
  • Ku Autoantigen