biostudies-literatureKuser-Abali GNIH/NCINCI NIH HHS3452-3457https://www.ebi.ac.uk/biostudies/studies/S-EPMC5879692biostudies-literatureUnknown115(13)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, Proceedings of the National Academy of Sciences of the United States of AmericaAn EZH2-mediated epigenetic mechanism behind p53-dependent tissue sensitivity to DNA damage.PMC5879692R01CA125144R01CA85679R01 CA125144R01CA167814R01 CA085679R01 CA167814Yuan ZMYan JLittle JBLim CBWilliamson ALiu QGong LMolloy MEHuang LKuser-Abali GZeng WfalseAn EZH2-mediated epigenetic mechanism behind p53-dependent tissue sensitivity to DNA damage.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, 2018-01-01T00:00:00Z2018 Mar2026-05-05T21:22:54.372Z2019-03-26T23:57:06ZS-EPMC58796922954056910.1073/pnas.1719532115