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ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses

Author

Listed:
  • Shideng Bao

    (Duke University Medical Center)

  • Randal S. Tibbetts

    (Duke University Medical Center)

  • Kathryn M. Brumbaugh

    (Duke University Medical Center)

  • Yanan Fang

    (Duke University Medical Center)

  • D. Ashley Richardson

    (Duke University Medical Center)

  • Ambereen Ali

    (Duke University Medical Center)

  • Susan M. Chen

    (Duke University Medical Center)

  • Robert T. Abraham

    (Duke University Medical Center)

  • Xiao-Fan Wang

    (Duke University Medical Center)

Abstract

Genotoxic stress triggers the activation of checkpoints that delay cell-cycle progression to allow for DNA repair1. Studies in fission yeast implicate members of the Rad family of checkpoint proteins, which includes Rad17, Rad1, Rad9 and Hus1, as key early-response elements during the activation of both the DNA damage and replication checkpoints2,3,4,5. Here we demonstrate a direct regulatory linkage between the human Rad17 homologue (hRad17) and the checkpoint kinases, ATM and ATR. Treatment of human cells with genotoxic agents induced ATM/ATR-dependent phosphorylation of hRad17 at Ser 635 and Ser 645. Overexpression of a hRad17 mutant (hRad17AA) bearing Ala substitutions at both phosphorylation sites abrogated the DNA-damage-induced G2 checkpoint, and sensitized human fibroblasts to genotoxic stress. In contrast to wild-type hRad17, the hRad17AA mutant showed no ionizing-radiation-inducible association with hRad1, a component of the hRad1–hRad9–hHus1 checkpoint complex. These findings demonstrate that ATR/ATM-dependent phosphorylation of hRad17 is a critical early event during checkpoint signalling in DNA-damaged cells.

Suggested Citation

  • Shideng Bao & Randal S. Tibbetts & Kathryn M. Brumbaugh & Yanan Fang & D. Ashley Richardson & Ambereen Ali & Susan M. Chen & Robert T. Abraham & Xiao-Fan Wang, 2001. "ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses," Nature, Nature, vol. 411(6840), pages 969-974, June.
    • Handle: RePEc:nat:nature:v:411:y:2001:i:6840:d:10.1038_35082110
    DOI: 10.1038/35082110
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