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

Genotoxic stress triggers the activation of checkpoints that delay cell-cycle progression to allow for DNA repair. 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 checkpoints. 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.

Pubmed ID: 11418864


  • Bao S
  • Tibbetts RS
  • Brumbaugh KM
  • Fang Y
  • Richardson DA
  • Ali A
  • Chen SM
  • Abraham RT
  • Wang XF



Publication Data

June 21, 2001

Associated Grants


Mesh Terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Line
  • DNA Damage
  • DNA-Binding Proteins
  • Doxycycline
  • Humans
  • Mice
  • Mutagens
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Serine
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins