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Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase

M L Agarwal1, A Agarwal, W R Taylor

  • 1Department of Molecular Biology, Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.

Oncogene
|August 28, 1997
PubMed

Insights

Poly-ADP-ribose polymerase (PARP) influences p53 protein levels but not its activity after DNA damage. PARP-null cells maintain normal p53-dependent functions, indicating PARP-independent p53 activation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Poly-ADP-ribose polymerase (PARP) and p53 are crucial for cellular responses to DNA damage.
  • Both proteins are induced by DNA damage and implicated in mediating normal cellular responses.

Purpose of the Study:

  • To investigate the relationship between PARP and p53 in DNA damage response pathways.
  • To determine if PARP influences p53 protein levels and/or activity.

Main Methods:

  • Utilized embryo fibroblasts from PARP-null mice and normal mouse cells.
  • Assessed p53 protein levels and induction in response to DNA damage and nucleotide depletion.
  • Measured p53 activity using a p53-responsive promoter.
  • Evaluated p53-dependent cellular checkpoints (G1 arrest, mitotic spindle checkpoint) and gene amplification.

Main Results:

  • PARP-null cells exhibited a twofold lower basal level of p53 and a greater than twofold reduction in p53 induction after DNA damage or nucleotide depletion.
  • The induced p53 protein level was 4-5 fold lower in PARP-deficient cells, but p53 activity remained largely unaffected.
  • PARP-deficient cells showed normal G1 arrest after DNA damage, unlike p53-null cells.
  • Mitotic spindle checkpoint and gene amplification permissivity were normal in PARP-deficient cells.

Conclusions:

  • The induced level of p53 protein is regulated by both PARP-dependent and PARP-independent pathways.
  • p53 activation as a transcription factor is largely independent of PARP.
  • Cellular responses mediated by p53, such as cell cycle arrest, are functional even with reduced p53 protein levels in PARP-deficient cells.

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