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Recovery from DNA damage checkpoint arrest by PP1-mediated inhibition of Chk1

Nicole R den Elzen1, Matthew J O'Connell

  • 1Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, A'Beckett St., Melbourne, VIC, Australia.

The EMBO Journal
|February 7, 2004
PubMed

Insights

The protein phosphatase Dis2 helps turn off the G2 DNA damage checkpoint by inactivating Chk1 kinase. This allows cells to re-enter the cell cycle after DNA repair.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The G2 DNA damage checkpoint prevents cell cycle progression during DNA repair.
  • Checkpoint activation involves Chk1 kinase upregulating Wee1 and downregulating Cdc25, inhibiting Cdc2.
  • Mechanisms for G2 checkpoint inactivation remain poorly understood.

Purpose of the Study:

  • To identify proteins involved in G2 DNA damage checkpoint release.
  • To investigate the role of Dis2 in G2 checkpoint regulation in Schizosaccharomyces pombe.

Main Methods:

  • Screening for genes whose overexpression causes premature mitotic entry under DNA damage conditions.
  • Assessing the effect of Dis2 overexpression and deletion on Chk1 phosphorylation and activity.
  • Evaluating the specificity of Dis2's role in the DNA damage checkpoint versus other cell cycle responses.

Main Results:

  • Overexpression of Dis2 leads to sensitivity to DNA damage and aberrant mitoses.
  • Dis2 abrogates Chk1 phosphorylation and activation in vivo and dephosphorylates Chk1 in vitro.
  • Dis2 deletion results in a prolonged Chk1-dependent G2 arrest and impaired checkpoint release.
  • Dis2's effects are specific to the DNA damage checkpoint.

Conclusions:

  • Dis2 is a key regulator of G2 DNA damage checkpoint inactivation.
  • Dis2 inactivates Chk1, facilitating mitotic entry after DNA repair.
  • This finding provides insight into cell cycle control following DNA damage.

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