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

Publication ,  Journal Article
Bao, S; Tibbetts, RS; Brumbaugh, KM; Fang, Y; Richardson, DA; Ali, A; Chen, SM; Abraham, RT; Wang, XF
Published in: Nature
June 21, 2001

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.

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Published In

Nature

DOI

ISSN

0028-0836

Publication Date

June 21, 2001

Volume

411

Issue

6840

Start / End Page

969 / 974

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Serine
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Mutagens
  • Mice
  • Humans
  • General Science & Technology
  • Doxycycline
 

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Bao, S., Tibbetts, R. S., Brumbaugh, K. M., Fang, Y., Richardson, D. A., Ali, A., … Wang, X. F. (2001). ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature, 411(6840), 969–974. https://doi.org/10.1038/35082110
Bao, S., R. S. Tibbetts, K. M. Brumbaugh, Y. Fang, D. A. Richardson, A. Ali, S. M. Chen, R. T. Abraham, and X. F. Wang. “ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses.Nature 411, no. 6840 (June 21, 2001): 969–74. https://doi.org/10.1038/35082110.
Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, et al. ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature. 2001 Jun 21;411(6840):969–74.
Bao, S., et al. “ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses.Nature, vol. 411, no. 6840, June 2001, pp. 969–74. Pubmed, doi:10.1038/35082110.
Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF. ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature. 2001 Jun 21;411(6840):969–974.
Journal cover image

Published In

Nature

DOI

ISSN

0028-0836

Publication Date

June 21, 2001

Volume

411

Issue

6840

Start / End Page

969 / 974

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Serine
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Mutagens
  • Mice
  • Humans
  • General Science & Technology
  • Doxycycline