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Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
10:24

Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins

Published on: September 28, 2012

DN-p73 is activated after DNA damage in a p53-dependent manner to regulate p53-induced cell cycle arrest

Stefania Vossio1, Emanuele Palescandolo, Natalia Pediconi

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

Oncogene
|May 29, 2002
PubMed

Insights

p53 protein activates a specific gene promoter (P2-p73Pr) following DNA damage. This leads to the accumulation of dominant-negative p73 (DN-p73), which then represses the P2-p73Pr, suggesting a role in terminating cellular responses.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • p53 and p73 are crucial tumor suppressor genes activated by DNA damage.
  • These genes induce cell cycle arrest or apoptosis based on damage severity.
  • Regulation of p53/p73 activity is vital for appropriate biological responses and cell cycle re-entry.

Purpose of the Study:

  • To investigate the role of p53 in regulating the P2-p73 promoter.
  • To explore the function of dominant-negative p73 (DN-p73) isoforms in response to DNA damage.
  • To elucidate the autoregulatory mechanisms controlling p53/p73 transcriptional activity.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assay to detect p53 binding in vivo.
  • Analysis of P2-p73 promoter activity in response to DNA damage.
  • Experiments using exogenous DN-p73alpha expression.
  • Studies in p73 knockout murine fibroblasts and human cells with p73 knockdown via siRNA.

Main Results:

  • p53 binds to and activates the P2-p73 promoter following non-apoptotic DNA damage (low-dose doxorubicin).
  • DN-p73alpha protein accumulates under these conditions.
  • Exogenous DN-p73alpha inhibits p53-mediated activation of the P2-p73 promoter.
  • P2-p73 promoter activation is significantly enhanced in p73-deficient cells.

Conclusions:

  • DN-p73 isoforms may participate in feedback loops that terminate p53/p73 responses in non-apoptotic cells.
  • p53-induced activation of the P2-p73 promoter and subsequent DN-p73 accumulation represent a novel regulatory mechanism.
  • These findings highlight the complex regulation of tumor suppressor gene activity following DNA damage.

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