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p21-Mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress

Fabienne Baus Charrier-Savournin1, Marie-Thérèse Château, Véronique Gire

  • 1CRBM-Centre National de la Recherche Scientifique FRE 2593, 34293 Montpellier, France.

Molecular Biology of the Cell
|June 8, 2004
PubMed

Insights

DNA damage triggers cell cycle arrest via p21, preventing mitosis. This protein retains inactive cyclin B1-Cdk1 complexes in the nucleus, blocking their activation and centrosome recruitment, ensuring cell cycle arrest.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Cell cycle arrest at G2 is vital for DNA damage repair, preventing genomic instability and oncogenesis.
  • The canonical model posits DNA damage inhibits cyclin B1-Cdk1 activation and nuclear import to block mitosis.

Purpose of the Study:

  • To investigate additional mechanisms employed by normal human fibroblasts to block cyclin B1-Cdk1 activation following DNA damage.
  • To elucidate the role of p21 in regulating mitotic entry after DNA damage.

Main Methods:

  • Analysis of cyclin B1-Cdk1 complex localization and activity in normal human fibroblasts with and without functional p21 following DNA damage induction.
  • Assessment of cyclin B1 recruitment to the centrosome and pRb phosphorylation status.

Main Results:

  • Normal fibroblasts accumulate inactive cyclin B1-Cdk1 complexes in the nucleus upon DNA damage, dependent on p21.
  • p21-deficient cells show nuclear exclusion of cyclin B1 and its centrosomal localization after DNA damage.
  • p21 prevents cyclin B1-Cdk1 activation by Cdc25 and Cdk-activating kinase and blocks pRb phosphorylation.

Conclusions:

  • p21 plays a dual role in DNA damage response: mediating cell cycle arrest and preventing premature mitosis.
  • p21 directly inhibits mitotic entry by maintaining cyclin B1-Cdk1 inactivation and promoting mitotic cyclin degradation.
  • These p21-dependent mechanisms establish a robust G2 arrest, crucial for preventing oncogenic transformation.

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