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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Richard A. Woo & Kevin G. McLure & Susan P. Lees-Miller & Derrick E. Rancourt & Patrick W. K. Lee, 1998. "DNA-dependent protein kinase acts upstream of p53 in response to DNA damage," Nature, Nature, vol. 394(6694), pages 700-704, August.
    • Handle: RePEc:nat:nature:v:394:y:1998:i:6694:d:10.1038_29343
    DOI: 10.1038/29343
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