ArticleProceedings of the National Academy of Sciences of the United States of America2018
An EZH2-mediated epigenetic mechanism behind p53-dependent tissue sensitivity to DNA damage.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- Refining treatment strategies for non-small cell lung cancer lacking actionable mutations: insights from multi-omics studies.British journal of cancer · 2025Review
- Modulatory Effect of Curcumin on Expression of Methyltransferase/Demethylase in Colon Cancer Cells: Impact on wt p53, mutp53 and c-Myc.Molecules (Basel, Switzerland) · 2025Article
- Targeting EZH2 in Cancer: Mechanisms, Pathways, and Therapeutic Potential.Molecules (Basel, Switzerland) · 2024Review
- Post-Translational Modifications (PTMs) of mutp53 and Epigenetic Changes Induced by mutp53.Biology · 2024Review
- PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.Journal of hepatology · 2024Article
- Review
- SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters.Cancers · 2023Article
- UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma.Oncogene · 2023Article
- Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer.Breast cancer research : BCR · 2022Article
- Article
- Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.Cell · 2020Article
- Mdm4 supports DNA replication in a p53-independent fashion.Oncogene · 2020Article
- The DNA Endonuclease Mus81 Regulates ZEB1 Expression and Serves as a Target of BET4 Inhibitors in Gastric Cancer.Molecular cancer therapeutics · 2019Article
- Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells.Molecular medicine reports · 2019Article
- The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma.Nature communications · 2019Article
- Abscopal Effect Following Proton Beam Radiotherapy in a Patient With Inoperable Metastatic Retroperitoneal Sarcoma.Frontiers in oncology · 2019Article
- Epigenetic mechanisms behind cellular sensitivity to DNA damage.Cell stress · 2018Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
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. Our work uncovers an epigenetic mechanism behind tissue sensitivity to DNA damage, carrying important translation implications.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.