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S phase cell-cycle arrest following DNA damage is independent of the p53/p21(WAF1) signalling pathway

F S Wyllie1, M F Haughton, J A Bond

  • 1CRC Thyroid Tumour Biology Group, Department of Pathology, University of Wales College of Medicine, Cardiff, UK.

Oncogene
|March 7, 1996
PubMed

Insights

The cyclin-kinase inhibitor p21 (WAF1/SD11) is crucial for p53-mediated cell cycle arrest after DNA damage. However, it is not essential for inhibiting DNA synthesis in S-phase cells following DNA strand breaks.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The cyclin-kinase inhibitor p21 (WAF1/SD11) is a known effector of p53-mediated cell-cycle arrest at the G(1)/S checkpoint.
  • In vitro studies suggest p21 may also inhibit DNA synthesis in S-phase cells.

Purpose of the Study:

  • To investigate the role of p21 (WAF1/SD11) in inhibiting DNA synthesis in intact cells after DNA damage.
  • To determine if p21 is essential for the acute inhibition of DNA replication in S-phase cells.

Main Methods:

  • Utilized normal human diploid fibroblasts with manipulated p53 function via a dominant-negative mutant (ala(143)) delivered by retroviral vector.
  • Induced DNA strand breaks using bleomycin in control and mutant p53-expressing cells.
  • Assessed cell-cycle progression, p21 (WAF1/SD11) induction, and DNA synthesis rates.

Main Results:

  • Bleomycin induced G(1)/S arrest, p21 (WAF1/SD11) upregulation, and reduced DNA synthesis in control cells.
  • Stable expression of mutant p53 abrogated G(1)/S arrest and p21 (WAF1/SD11) induction but did not affect S-phase DNA synthesis inhibition.
  • Mutant p53 did not significantly impact the inhibition of DNA replication in S-phase nuclei.

Conclusions:

  • p21 (WAF1/SD11) induction is not essential for the acute inhibition of DNA synthesis in intact cells following DNA strand breaks in S phase.
  • The findings challenge the in vitro evidence suggesting p21's critical role in inhibiting DNA replication in S-phase cells.

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