DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes

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Quantitative Detection of DNA-Protein Crosslinks and Their Post-Translational Modifications

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Antonio Costanzo1, Paola Merlo, Natalia Pediconi

  • 1Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome La Sapienza, 00161, Rome, Italy.

Molecular Cell
|January 24, 2002
PubMed

Insights

DNA damage triggers p73 acetylation by p300, enhancing apoptosis. This acetylation is crucial for p73

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor p53 and its relative p73 are activated by DNA damage.
  • Activation leads to cell cycle arrest or apoptosis.
  • The precise mechanisms regulating p73's apoptotic function are under investigation.

Purpose of the Study:

  • To investigate the role of p73 acetylation in response to DNA damage.
  • To elucidate the involvement of the acetyltransferase p300 and protooncogene c-abl in p73 acetylation.
  • To determine the impact of p73 acetylation on the transcriptional regulation of proapoptotic genes.

Main Methods:

  • Studied DNA damage-induced acetylation of p73.
  • Assessed the effect of inhibiting p300 enzymatic activity on apoptosis in p53(-/-) cells.
  • Analyzed the transcriptional activity of a nonacetylatable p73 mutant on target genes like p53AIP1 and p21.
  • Investigated the requirement of c-abl in p300-mediated p73 acetylation.

Main Results:

  • DNA damage induces p73 acetylation by the acetyltransferase p300.
  • Inhibition of p300 hampers apoptosis in a p53-deficient background.
  • A nonacetylatable p73 mutant shows defects in transcribing the proapoptotic gene p53AIP1 but not p21.
  • p300-mediated acetylation of p73 requires the protooncogene c-abl.

Conclusions:

  • DNA damage-induced acetylation potentiates p73's apoptotic function.
  • Acetylation enhances p73's ability to selectively activate proapoptotic target genes.
  • The p300/c-abl pathway is critical for mediating p73 acetylation and its proapoptotic role.

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