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

Significance p53 is widely perceived as a determinant of sensitivity to radio-/chemotherapy. We report a distinct mechanism whereby p53-regulated MDM2 works together with MDMX to modulate sensitivity to DNA damage by controlling EZH2 (enhancer of zeste homolog 2) turnover. Our work uncovers a mechanism of chromatin modification underlying tissue sensitivity to DNA damage. The MDM2/MDMX disruptor can be used for protecting renewable tissues from chemo-/radiotherapy-induced damage, and the EZH2 inhibitor for sensitizing p53-mutant cancer cells to chemo-/radiotherapy. 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.