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Recovery from a DNA-damage-induced G2 arrest requires Cdk-dependent activation of FoxM1

Mónica Alvarez-Fernández1, Vincentius A Halim, Lenno Krenning

  • 1Department of Medical Oncology, UMC Utrecht, Universiteitsweg 100, Stratenum 2.118, Utrecht 3584 CG, The Netherlands.

EMBO Reports
|April 10, 2010
PubMed

Insights

DNA-damage checkpoints halt cell division but require cyclin-dependent kinase (Cdk) activity to maintain the transcription factor FoxM1 for cell-cycle recovery. Sufficient Cdk levels are crucial for cells to resume division after DNA damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • DNA-damage checkpoints arrest the cell cycle by inhibiting cyclin-dependent kinase (Cdk) complexes.
  • The transcription factor FoxM1 regulates gene expression during the G2 phase and its activation depends on Cdk activity.

Purpose of the Study:

  • To investigate the role of FoxM1 during DNA-damage-induced G2 arrest.
  • To understand the paradoxical requirement of Cdk activity for FoxM1-dependent transcription during cell-cycle arrest.

Main Methods:

  • Analysis of FoxM1 transcriptional activity during G2 arrest.
  • Assessment of Cdk activity levels and their impact on FoxM1 targets.
  • Evaluation of cellular competence for checkpoint recovery.

Main Results:

  • FoxM1 remains transcriptionally active during DNA-damage-induced G2 arrest and is essential for checkpoint recovery.
  • Cdk activity, despite being reduced, is necessary to sustain FoxM1-dependent transcription and expression of pro-mitotic genes (cyclin A, cyclin B, Plk1).
  • Sufficient Cdk activity during the DNA-damage response is vital for cells to recover from DNA damage.

Conclusions:

  • FoxM1 plays a critical role in maintaining cellular competence for checkpoint recovery after DNA damage.
  • A basal level of Cdk activity is paradoxically required to support FoxM1-mediated transcription during DNA-damage-induced arrest.
  • Maintaining adequate Cdk activity is essential for cells to overcome DNA damage and resume cell-cycle progression.

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