MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53

Magdalena Wienken, Antje Dickmanns, Alice Nemajerova, Daniela Kramer, Zeynab Najafova, Miriam Weiss, Oleksandra Karpiuk, Moustapha Kassem, Yanping Zhang, Guillermina Lozano, Steven A. Johnsen, Ute M. Moll, Xin Zhang, Matthias Dobbelstein

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53. MDM2 antagonizes the tumor suppressor p53. Wienken et al. report that MDM2 supports the Polycomb Repressor Complex 2 (PRC2), independent of p53. MDM2 thereby supports gene repression, stemness, and cancer cell survival, enhancing histone H2AK119 monoubiquitination and H3K27 trimethylation. MDM2 thus controls p53 and PRC2, each central decision-makers of cell fate.

Original languageEnglish (US)
Pages (from-to)68-83
Number of pages16
JournalMolecular Cell
Volume61
Issue number1
DOIs
StatePublished - Jan 7 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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