A role for ATR in the DNA damage-induced phosphorylation of p53

  1. Randal S. Tibbetts,
  2. Kathryn M. Brumbaugh,
  3. Josie M. Williams,
  4. Jann N. Sarkaria,
  5. William A. Cliby,
  6. Sheau-Yann Shieh,
  7. Yoichi Taya,
  8. Carol Prives, and
  9. Robert T. Abraham
  1. Department of Pharmacology and Cancer Cell Biology, Duke University, Durham, North Carolina 27710 USA; Division of Oncology Research, Mayo Clinic and Foundation, Rochester, Minnesota 55902 USA; Department of Biological Sciences, Columbia University, New York, New York 10027 USA; National Cancer Center Research Institute, Tokyo, Japan

Abstract

Phosphorylation at Ser-15 may be a critical event in the up-regulation and functional activation of p53 during cellular stress. In this report we provide evidence that the ATM–Rad3-related protein ATR regulates phosphorylation of Ser-15 in DNA-damaged cells. Overexpression of catalytically inactive ATR (ATRki) in human fibroblasts inhibited Ser-15 phosphorylation in response to γ-irradiation and UV light. In γ-irradiated cells, ATRkiexpression selectively interfered with late-phase Ser-15 phosphorylation, whereas ATRki blocked UV-induced Ser-15 phosphorylation in a time-independent manner. ATR phosphorylated p53 at Ser-15 and Ser-37 in vitro, suggesting that p53 is a target for phosphorylation by ATR in DNA-damaged cells.

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Footnotes

  • Corresponding author:

  • E-MAIL abrah008{at}mc.duke.edu; FAX (919) 684-8922.

    • Received November 9, 1998.
    • Accepted December 3, 1998.
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