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Molecular and Cellular Biology, June 2000, p. 3772-3780, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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

Dae-Sik Lim,1,dagger Hannes Vogel,2 Dennis M. Willerford,3 Arthur T. Sands,1 Kenneth A. Platt,1 and Paul Hasty1,*

Lexicon Genetics, The Woodlands, Texas 77381-42871; Department of Pathology, Baylor College of Medicine, Houston, Texas 770302; and Departments of Medicine and Immunology, University of Washington, Seattle, Washington 981953

Received 24 January 2000/Returned for modification 23 February 2000/Accepted 6 March 2000

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 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.

* Corresponding author. Mailing address: Lexicon Genetics, 4000 Research Forest Dr., The Woodlands, TX 77381-4287. Phone: (281) 364-0100. Fax: (281) 364-0155. E-mail: phasty{at}lexgen.com.

dagger Present address: Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794.

Molecular and Cellular Biology, June 2000, p. 3772-3780, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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