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DNA-dependent protein kinase is not required for the p53-dependent response to DNA damage

Author

Listed:
  • Gretchen S. Jimenez

    (Gene Expression Laboratory, The Salk Institute)

  • Fredrik Bryntesson

    (Trafford Centre, University of Sussex
    Laboratory of Cell Biology, National Cancer Institute, National Institute of Health)

  • Maria I. Torres-Arzayus

    (Boston University School of Medicine)

  • Anne Priestley

    (Boston University School of Medicine)

  • Michelle Beeche

    (Gene Expression Laboratory, The Salk Institute)

  • Shin'ichi Saito

    (MRC Cell Mutation Unit, University of Sussex)

  • Kazuyasu Sakaguchi

    (MRC Cell Mutation Unit, University of Sussex)

  • Ettore Appella

    (MRC Cell Mutation Unit, University of Sussex)

  • Penny A. Jeggo

    (Boston University School of Medicine)

  • Guillermo E. Taccioli

    (Trafford Centre, University of Sussex)

  • Geoffrey M. Wahl

    (Gene Expression Laboratory, The Salk Institute)

  • Michael Hubank

Abstract

Damage to DNA in the cell activates the tumour-suppressor protein p53 (ref. 1), and failure of this activation leads to genetic instability and a predisposition to cancer. It is therefore crucial to understand the signal transduction mechanisms that connect DNA damage with p53 activation. The enzyme known as DNA-dependent protein kinase (DNA-PK) has been proposed to be an essential activator of p53 (refs 2, 3), but the evidence for its involvement in this pathway is controversial3,4. We now show that the p53 response is fully functional in primary mouse embryonic fibroblasts lacking DNA-PK: irradiation-induced DNA damage in these defective fibroblasts induces a normal response of p53 accumulation, phosphorylation of a p53 serine residue at position 15, nuclear localization and binding to DNA of p53. The upregulation of p53-target genes and cell-cycle arrest also occur normally. The DNA-PK-deficient cell line SCGR11 contains a homozygous mutation in the DNA-binding domain of p53, which may explain the defective response by p53 reported in this line3. Our results indicate that DNA-PK activity is not required for cells to mount a p53-dependent response to DNA damage.

Suggested Citation

  • Gretchen S. Jimenez & Fredrik Bryntesson & Maria I. Torres-Arzayus & Anne Priestley & Michelle Beeche & Shin'ichi Saito & Kazuyasu Sakaguchi & Ettore Appella & Penny A. Jeggo & Guillermo E. Taccioli &, 1999. "DNA-dependent protein kinase is not required for the p53-dependent response to DNA damage," Nature, Nature, vol. 400(6739), pages 81-83, July.
    • Handle: RePEc:nat:nature:v:400:y:1999:i:6739:d:10.1038_21913
    DOI: 10.1038/21913
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