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Caspase-2 is required for DNA damage-induced expression of the CDK inhibitor p21(WAF1/CIP1)

D Sohn1, W Budach, R U Jänicke

  • 1Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.

Cell Death and Differentiation
|April 9, 2011
PubMed

Insights

Caspase-2 regulates p21 protein levels at the translational level, impacting DNA damage responses and cell fate. This function is independent of its enzymatic activity and known activation platforms.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Caspase-2 is a highly conserved caspase with an incompletely understood function.
  • p21 is a key regulator of cell cycle arrest and senescence.

Purpose of the Study:

  • To elucidate the precise function of caspase-2 in cellular responses to DNA damage.
  • To investigate the mechanism by which caspase-2 influences p21 expression.

Main Methods:

  • Knockdown and overexpression of caspase-2 in various cell types.
  • Analysis of p21 mRNA transcription and protein levels.
  • Assessment of p21 reporter constructs with 3'-UTR sequences.
  • Evaluation of γ-IR-induced senescence and apoptosis.

Main Results:

  • Caspase-2 knockdown impaired DNA damage-induced p21 expression.
  • Caspase-2 regulates p21 at the translational level, not transcriptional.
  • Overexpression of a caspase-2 mutant increased p21 levels.
  • Caspase-2's role in p21 regulation is independent of its enzymatic activity and known activating platforms like RAIDD, RIP, or DNA-PKcs.
  • Caspase-2 depletion prevented p21 expression, reverting senescence to apoptosis.

Conclusions:

  • Caspase-2 functions as a novel translational regulator of p21 expression.
  • This regulatory role is crucial for the cellular response to DNA damage, influencing cell fate decisions between senescence and apoptosis.
  • The mechanism is independent of caspase-2's enzymatic activity and canonical activation pathways.

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