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Molecular and Cellular Biology, June 2000, p. 4075-4083, Vol. 20, No. 11
0270-7306/00/$04.00+0

The p53 Response to DNA Damage In Vivo Is Independent of DNA-Dependent Protein Kinase

Chamelli Jhappan,1,* Timur M. Yusufzai,1 Stacie Anderson,2 Miriam R. Anver,3 and Glenn Merlino1

Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-42551; Pathology/Histotechnology Laboratory, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 217023; and Laboratory of Gene Transfer, NHGRI, National Institutes of Health, Bethesda, Maryland 20892-44422

Received 16 June 1999/Returned for modification 22 July 1999/Accepted 28 February 2000

Ionizing radiation (IR) exposure causes mammalian cells to undergo p53-dependent cell cycle arrest and/or apoptosis. The in vivo role of DNA-dependent protein kinase (DNA-PK) in the transduction of the DNA damage signal to p53 remains unresolved. To determine the relationship between DNA-PK and p53, we studied the cell cycle and apoptotic responses to IR in mice deficient in DNA-PK. Using the slip mouse, which harbors an inactivating mutation of the DNA-PK catalytic subunit (DNA-PKcs), we demonstrated not only that these DNA-PKcs null mutants were highly radiosensitive but also that upon IR treatment, p53 accumulated in their cultured cells and tissue. Induced p53 was transcriptionally active and mediated the induction of p21 and Bax in slip cells. Examination of the thymic cell cycle response to IR treatment indicated that the slip G1/S-phase cell cycle checkpoint function was intact. We further show that slip mice exhibited a higher level of spontaneous thymic apoptosis as well as a more robust apoptotic response to IR than wild-type mice. Together, these data demonstrate that the p53-mediated response to DNA damage is intact in cells devoid of DNA-PK activity and suggest that other kinases, such as the product of the gene (ATM) mutated in ataxia telangiectasia, are better candidates for regulating IR-induced phosphorylation and accumulation of p53.

* Corresponding author. Mailing address: Laboratory of Molecular Biology, NCI, NIH, Building 37, Room 2E22, 37 Convent Dr. MSC4255, Bethesda, MD 20892-4255. Phone: (301) 496-4620. Fax: (301) 480-7618. E-mail: cjhappan{at}helix.nih.gov.

Molecular and Cellular Biology, June 2000, p. 4075-4083, Vol. 20, No. 11
0270-7306/00/$04.00+0


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