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

S Bao1, R S Tibbetts, K M Brumbaugh

  • 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Nature
|June 22, 2001
PubMed

Insights

Genotoxic stress activates cell cycle checkpoints for DNA repair. Human Rad17 (hRad17) phosphorylation by ATM/ATR kinases is crucial for this DNA damage response, regulating cell cycle arrest and DNA repair signaling.

Area of Science:

  • Cellular biology
  • Molecular genetics
  • Biochemistry

Background:

  • Genotoxic stress activates cell cycle checkpoints to facilitate DNA repair.
  • The Rad family of checkpoint proteins, including Rad17, Rad1, Rad9, and Hus1, are critical for DNA damage and replication checkpoint activation in fission yeast.
  • The precise role of human Rad17 (hRad17) in DNA damage response pathways requires further elucidation.

Purpose of the Study:

  • To investigate the regulatory linkage between human Rad17 (hRad17) and the ATM and ATR checkpoint kinases.
  • To determine the functional significance of hRad17 phosphorylation at specific sites in response to genotoxic stress.
  • To elucidate the role of hRad17 in the DNA-damage-induced G2 checkpoint and its association with checkpoint protein complexes.

Main Methods:

  • Treatment of human cells with genotoxic agents.
  • Analysis of hRad17 phosphorylation at Ser 635 and Ser 645 by ATM/ATR kinases.
  • Overexpression of wild-type hRad17 and a phosphorylation-deficient mutant (hRad17AA).
  • Assessment of G2 checkpoint abrogation and cellular sensitivity to genotoxic stress.
  • Investigation of hRad17 association with hRad1 using co-immunoprecipitation assays.

Main Results:

  • Genotoxic agents induced ATM/ATR-dependent phosphorylation of hRad17 at Ser 635 and Ser 645 in human cells.
  • Overexpression of the hRad17AA mutant abrogated the DNA-damage-induced G2 checkpoint.
  • The hRad17AA mutant sensitized human fibroblasts to genotoxic stress.
  • The hRad17AA mutant failed to associate with hRad1 following ionizing radiation, unlike wild-type hRad17.

Conclusions:

  • ATM/ATR-dependent phosphorylation of hRad17 at Ser 635 and Ser 645 is a critical early event in DNA damage checkpoint signaling.
  • This phosphorylation event is essential for the proper activation of the G2 checkpoint and cellular resistance to genotoxic stress.
  • hRad17 phosphorylation regulates its interaction with the hRad1-hRad9-hHus1 checkpoint complex, highlighting its central role in DNA repair pathways.

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