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Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress

Simon S McDade1, Daksha Patel2, Michael Moran2

  • 1Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, UK s.mcdade@qub.ac.uk.

Nucleic Acids Research
|May 15, 2014
PubMed

Insights

TP53 and TP63 proteins interact to regulate cell cycle and apoptosis under genotoxic stress. This study reveals their distinct binding patterns and gene regulatory roles, impacting DNA repair and cell proliferation.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • TP53 is a tumor suppressor activated by genotoxic stress to induce cell cycle arrest or apoptosis.
  • TP63 can repress TP53's canonical functions in normal epithelia and drive proliferation in squamous cell carcinomas.
  • Understanding the interplay between TP53 and TP63 is crucial for cancer research.

Purpose of the Study:

  • To define the genome-wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells.
  • To elucidate the distinct binding patterns and regulatory mechanisms of TP53 and TP63.
  • To investigate the role of TP63 in maintaining DNA repair gene expression.

Main Methods:

  • Chromatin immunoprecipitation sequencing (ChIP-sequencing).
  • Microarray analysis.
  • Genomic and transcriptomic analyses to define TP53 and TP63 cistromes and gene expression profiles.

Main Results:

  • TP53 and TP63 bind to overlapping yet distinct genomic sites with unique consensus motifs.
  • Cisplatin and adriamycin induce differential binding events for TP53 and TP63.
  • TP53 modulates TP63 activity, leading to global repression of cell cycle progression, mitosis, and DNA repair, alongside activation of pro-apoptotic genes.
  • TP63 is essential for maintaining DNA repair gene expression in the absence of stress.

Conclusions:

  • TP53 and TP63 exhibit complex genome-wide interactions that dictate cellular responses to genotoxic stress.
  • The interplay between TP53 and TP63 influences cell cycle, apoptosis, and DNA repair pathways.
  • TP63 plays a critical role in maintaining genomic stability through regulation of DNA repair genes.

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