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A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase

A Blasina1, I V de Weyer, M C Laus

  • 1Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Current Biology : CB
|January 16, 1999
PubMed
Abstract

Insights

DNA damage triggers inactivation of the Cdc25 phosphatase in human cells. This process is mediated by novel kinases, Cds1 and Chk1, crucial for the DNA-damage checkpoint.

Area of Science:

  • Cell cycle regulation
  • DNA damage response
  • Kinase signaling pathways

Background:

  • Cdc2 kinase activity is regulated by phosphorylation at Thr14/Tyr15.
  • Wee1/Myt1 kinases and Cdc25 phosphatase oppose each other in regulating Cdc2 phosphorylation.
  • Proper regulation of these enzymes is vital for the G2-M DNA-damage checkpoint.

Purpose of the Study:

  • To investigate the regulation of Cdc25 phosphatase activity in response to DNA damage.
  • To identify kinases involved in the inactivation of Cdc25 following DNA damage.

Main Methods:

  • Exposure of human cells to ionizing radiation.
  • Assay of Cdc25 phosphatase activity.
  • Inhibition studies using wortmannin (a PI 3-kinase inhibitor).
  • Identification and characterization of human kinases phosphorylating Cdc25 in vitro.

Main Results:

  • Ionizing radiation decreased Cdc25 activity.
  • Wortmannin suppressed the irradiation-induced decrease in Cdc25 activity.
  • The DNA-damage response was dependent on the ataxia telangiectasia gene.
  • Two human kinases, Chk1 and a novel Cds1 homolog, were identified that phosphorylate and inactivate Cdc25.
  • Human Cds1 kinase activity increased upon DNA damage.

Conclusions:

  • The DNA-damage checkpoint in human cells involves direct inactivation of Cdc25.
  • This inactivation is catalyzed by Cds1 and/or Chk1 kinases.
  • These findings elucidate a key mechanism in the cellular response to DNA damage.

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