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An EZH2-mediated epigenetic mechanism behind p53-dependent tissue sensitivity to DNA damage

Gamze Kuser-Abali1, Lu Gong1, Jiawei Yan1

  • 1John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|March 16, 2018
PubMed

Insights

Renewable tissues

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • Renewable tissues are sensitive to DNA damage, potentially due to high p53 levels.
  • Cell proliferation necessitates p53 down-regulation, creating a paradox in DNA damage sensitivity.
  • Understanding this discrepancy is crucial for protecting tissues during cancer therapy.

Purpose of the Study:

  • To investigate the epigenetic mechanism regulating DNA damage sensitivity in renewable tissues.
  • To identify the role of p53, MDM2, MDMX, and EZH2 in this process.
  • To explore therapeutic strategies for protecting tissues from genotoxic stress.

Main Methods:

  • Utilized genetic mouse models and pharmacologic inhibitors.
  • Investigated the interaction between MDM2, MDMX, and EZH2.
  • Assessed the impact of EZH2 on chromatin compaction (H3K27me3) and DNA damage sensitivity.
  • Examined p53-mutated cells to understand resistance mechanisms.

Main Results:

  • p53-regulated MDM2, with MDMX, targets EZH2 for degradation, controlling DNA damage sensitivity.
  • EZH2, a methyltransferase, promotes H3K27me3 and chromatin compaction, influencing DNA damage response.
  • Inhibiting the MDM2-MDMX interaction stabilizes EZH2, protecting tissues from radio-/chemotherapy injury.
  • Diminished MDM2 in p53-mutated cells leads to EZH2 accumulation and treatment resistance.

Conclusions:

  • Uncovered an epigenetic mechanism involving EZH2 in tissue sensitivity to DNA damage.
  • MDM2-MDMX-EZH2 axis regulates chromatin compaction and DNA damage response.
  • Targeting this axis offers a potential strategy to protect renewable tissues during cancer therapy.
  • Findings have significant translational implications for improving cancer treatment outcomes.
Keywords:
DNA damage sensitivityEZH2chromatin architectureepigenetic modificationsp53/MDM2/MDMX

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