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

Shideng Bao, Randal S. Tibbetts, Kathryn M. Brumbaugh, Yanan Fang, D. Ashley Richardson, Ambereen Ali, Susan M. Chen, Robert T. Abraham and Xiao-Fan Wang ()
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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

Nature, 2001, vol. 411, issue 6840, 969-974

Abstract: 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.

Date: 2001
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DOI: 10.1038/35082110

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