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Heterochromatin silencing of p53 target genes by a small viral protein

Conrado Soria1, Fanny E Estermann, Kristen C Espantman

  • 1Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037-1099, USA.

Nature
|August 27, 2010
PubMed

Insights

Adenovirus protein E4-ORF3 silences the tumor suppressor p53 (also known as TP53) via an epigenetic mechanism. This novel pathway, independent of p53 stabilization, involves forming a nuclear structure that blocks p53 binding to DNA.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Virology

Background:

  • The tumor suppressor p53 (TP53) is crucial for preventing cancer and viral replication, typically inactivated in most cancers.
  • p53-mediated transcription is generally linked to its stabilization upon DNA damage or oncogene activation.
  • Adenovirus protein E1B-55k inactivates p53 by degradation, forming the basis for current p53-selective cancer therapies.

Purpose of the Study:

  • To elucidate the mechanism by which adenovirus E4-ORF3 protein inactivates p53-activated transcription.
  • To investigate the role of epigenetic modifications in p53 inactivation during adenovirus infection.
  • To explore novel strategies for p53-selective oncolytic viral therapies.

Main Methods:

  • Investigated the interaction between adenovirus E4-ORF3 and p53.
  • Utilized chromatin immunoprecipitation assays to analyze histone modifications at p53 target promoters.
  • Assessed p53-DNA binding and transcriptional activity in the presence of E4-ORF3.

Main Results:

  • Adenovirus E4-ORF3 protein induces de novo H3K9me3 heterochromatin formation at p53 target promoters.
  • This epigenetic silencing prevents p53-DNA binding, irrespective of p53 phosphorylation and stabilization.
  • E4-ORF3 forms a selective nuclear structure that inactivates p53, distinct from E1B-55k-mediated degradation.

Conclusions:

  • Adenovirus E4-ORF3 employs a dominant epigenetic mechanism to silence p53, independent of p53 stabilization.
  • This finding reveals a novel pathway for p53 inactivation in cancer and viral infections.
  • The study provides insights for developing advanced p53-selective oncolytic viral therapies targeting epigenetic silencing.

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