Title: MDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output
Authors: Chen, Lihong ×
Zwolinska, Aleksandra K
Smith, Matthew A
Cross, Brittany
Koomen, John
Yuan, Zhi-Min
Jenuwein, Thomas
Marine, Chris
Wright, Kenneth L
Chen, Jiandong #
Issue Date: Aug-2010
Publisher: Nature Publishing Group
Series Title: EMBO Journal vol:29 issue:15 pages:2538-2552
Abstract: MDM2 is a key regulator of the p53 tumor suppressor acting primarily as an E3 ubiquitin ligase to promote its degradation. MDM2 also inhibits p53 transcriptional activity by recruiting histone deacetylase and corepressors to p53. Here, we show that immunopurified MDM2 complexes have significant histone H3-K9 methyltransferase activity. The histone methyltransferases SUV39H1 and EHMT1 bind specifically to MDM2 but not to its homolog MDMX. MDM2 mediates formation of p53-SUV39H1/EHMT1 complex capable of methylating H3-K9 in vitro and on p53 target promoters in vivo. Furthermore, MDM2 promotes EHMT1-mediated p53 methylation at K373. Knockdown of SUV39H1 and EHMT1 increases p53 activity during stress response without affecting p53 levels, whereas their overexpression inhibits p53 in an MDM2-dependent manner. The p53 activator ARF inhibits SUV39H1 and EHMT1 binding to MDM2 and reduces MDM2-associated methyltransferase activity. These results suggest that MDM2-dependent recruitment of methyltransferases is a novel mechanism of p53 regulation through methylation of both p53 itself and histone H3 at target promoters.
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Molecular Cancer Biology (VIB-KU Leuven Centre for Cancer Biology)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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