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

Gamze Kuser-Abali, Lu Gong, Jiawei Yan, Qingqing Liu, Weiqi Zeng, Amanda Williamson, Chuan Bian Lim, Mary Ellen Molloy, John B. Little, Lei Huang, Zhi Min Yuan

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation. As a methyltransferase, EZH2 promotes H3K27me3, and therefore chromatin compaction, to determine sensitivity to DNA damage. We demonstrate that genetic and pharmacologic interference of the association between MDM2 and MDMX stabilizes EZH2, resulting in protection of renewable tissues from radio-/chemotherapy-induced acute injury. In cells with p53 mutation, there are diminished MDM2 levels, and thus accumulation of EZH2, underpinning the resistant phenotype. Ourwork uncovers an epigeneticmechanism behind tissue sensitivity to DNA damage, carrying important translation implications.

Original languageEnglish
Pages (from-to)3452-3457
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number13
DOIs
Publication statusPublished - 27 Mar 2018
Externally publishedYes

Keywords

  • Chromatin architecture
  • DNA damage sensitivity
  • Epigenetic modifications
  • EZH2
  • P53/MDM2/MDMX

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