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

S. Bao, R. S. Tibbetts, K. M. Brumbaugh, Yanan Fang, D. A. Richardson, A. Ali, S. M. Chen, R. T. Abraham, X. F. Wang

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)969-974
Number of pages6
JournalNature
Volume411
Issue number6840
DOIs
StatePublished - Jun 21 2001
Externally publishedYes

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Phosphorylation
DNA Damage
Schizosaccharomyces
Response Elements
Cell Cycle Checkpoints
Ionizing Radiation
DNA Replication
DNA Repair
Phosphotransferases
Fibroblasts
DNA
Proteins

ASJC Scopus subject areas

  • General

Cite this

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 responses. Nature, 411(6840), 969-974. https://doi.org/10.1038/35082110

ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic responses. / Bao, S.; Tibbetts, R. S.; Brumbaugh, K. M.; Fang, Yanan; Richardson, D. A.; Ali, A.; Chen, S. M.; Abraham, R. T.; Wang, X. F.

In: Nature, Vol. 411, No. 6840, 21.06.2001, p. 969-974.

Research output: Contribution to journalArticle

Bao, S, Tibbetts, RS, Brumbaugh, KM, Fang, Y, Richardson, DA, Ali, A, Chen, SM, Abraham, RT & Wang, XF 2001, 'ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic responses', Nature, vol. 411, no. 6840, pp. 969-974. 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 responses. Nature. 2001 Jun 21;411(6840):969-974. https://doi.org/10.1038/35082110
Bao, S. ; Tibbetts, R. S. ; Brumbaugh, K. M. ; Fang, Yanan ; Richardson, D. A. ; Ali, A. ; Chen, S. M. ; Abraham, R. T. ; Wang, X. F. / ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic responses. In: Nature. 2001 ; Vol. 411, No. 6840. pp. 969-974.
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