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

• DOI: 10.1016/j.molcel.2015.12.008
• Publication Date: 2015-12-31T20:41:19Z
• Authors: 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
• Keywords: Time Factors; Mesenchymal Stem Cells/metabolism; Cell Survival; Polycomb Repressive Complex 2/genetics; Induced Pluripotent Stem Cells; Histones/metabolism; Transfection; Methylation; Histones; Mice; Polycomb Repressive Complex 1/metabolism; Neoplastic Stem Cells/metabolism; Ubiquitin-Protein Ligases/metabolism; Osteogenesis; Animals; Humans; Proto-Oncogene Proteins c-mdm2/genetics; Cell Lineage; Molecular Biology; Cell Proliferation; Polycomb Repressive Complex 1; Neoplastic; Ubiquitination; Polycomb Repressive Complex 2; Cell Differentiation; Mesenchymal Stem Cells; Cell Biology; Chromatin Assembly and Disassembly; HCT116 Cells; Gene Expression Regulation, Neoplastic; Induced Pluripotent Stem Cells/metabolism; Phenotype; Gene Expression Regulation; MCF-7 Cells; Neoplastic Stem Cells; RNA Interference; Tumor Suppressor Protein p53/genetics; Signal Transduction

SummaryThe 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.