DNA-dependent protein kinase acts upstream of p53 in response to DNA damage

Richard A. Woo, Kevin G. McLure, Susan P. Lees-Miller, Derrick E. Rancourt and Patrick W. K. Lee ()
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Richard A. Woo: Departments of Microbiology and Infectious Diseases
Kevin G. McLure: Departments of Microbiology and Infectious Diseases
Susan P. Lees-Miller: Biological Sciences
Derrick E. Rancourt: Biochemistry and Molecular Biology, University of Calgary
Patrick W. K. Lee: Departments of Microbiology and Infectious Diseases

Nature, 1998, vol. 394, issue 6694, 700-704

Abstract: Abstract The tumour suppressor p53 becomes activated as a transcription factor in response to DNA damage1,2,3, but the mechanism for this activation is unclear. A good candidate for an upstream activator of p53 is the DNA-dependent protein kinase (DNA-PK) that depends on the presence of DNA breaks for its activity4,5,6. Here we investigate the link between DNA damage and the activation of DNA-PK and of p53. To determine whether DNA-PK is an upstream mediator of the p53 DNA-damage response, we analysed a severe combined-immunodeficiency (SCID) mouse cell line, SCGR11 (refs 7, 8), and the human glioma cell line M059J (ref. 9). Both cell lines lack any detectable DNA-PK activity. We find that p53 is incapable of binding to DNA in the absence of DNA-PK, that DNA-PK is necessary but not sufficient for activation of p53 sequence-specific DNA binding, and that this activation occurs in response to DNA damage. Our results establish DNA-PK as a link between DNA damage and p53 activation, and reveal the existence of a mammalian DNA-damage-response pathway.

Date: 1998
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DOI: 10.1038/29343

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