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Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit

Van Leung-Pineda1, Christine E Ryan, Helen Piwnica-Worms

  • 1Department of Cell Biology and Physiology & Howard Hughes Medical Institute, Washington University School of Medicine, Box 8228, 660 South Euclid Ave., St. Louis, MO 63110, USA.

Molecular and Cellular Biology
|October 4, 2006
PubMed

Insights

Checkpoint kinase 1 (Chk1) activity is regulated by ATR and PP2A phosphatases. This ATR-Chk1-PP2A circuit maintains low Chk1 activity during normal cell cycles, ensuring rapid response to genotoxic stress.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Checkpoint kinase 1 (Chk1) is crucial for cell cycle and checkpoint control in eukaryotes.
  • Chk1 targets Cdc25A for degradation, a key step in DNA damage response.
  • Chk1 phosphorylation at S317/S345 by ATR indicates activation during genotoxic stress.

Purpose of the Study:

  • Investigate the regulation of Chk1 activity and phosphorylation.
  • Elucidate the role of ATR and protein phosphatase 2A (PP2A) in Chk1 regulation.
  • Understand the mechanism maintaining Chk1 activity during unperturbed cell cycles.

Main Methods:

  • In vivo studies of Chk1 phosphorylation.
  • Inhibition of Chk1 kinase activity.
  • Analysis of ATR and PP2A interactions with Chk1.

Main Results:

  • Inhibition of Chk1 kinase activity paradoxically increased Chk1 phosphorylation at S317/S345.
  • ATR was confirmed to phosphorylate Chk1 under Chk1 inhibition.
  • PP2A antagonizes ATR-mediated Chk1 phosphorylation.
  • PP2A dephosphorylation of Chk1 is regulated by Chk1's own kinase activity.

Conclusions:

  • A novel regulatory circuit involving ATR, Chk1, and PP2A maintains Chk1 in a low-activity state during normal cell division.
  • This ATR-Chk1-PP2A circuit ensures Chk1 is primed for rapid activation upon genotoxic stress.
  • Understanding this circuit provides insights into cell cycle control and DNA damage response pathways.

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