Lee, Chul-Hwan, Yu, Jia-Ray, Kumar, Sunil, Jin, Ying, LeRoy, Gary, Bhanu, Natarajan, Kaneko, Syuzo, Garcia, Benjamin A., Hamilton, Andrew D., Reinberg, Danny (May 2018) Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin. Molecular Cell, 70 (3). pp. 422-434. ISSN 1097-2765
Abstract
Summary PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifested little activity in vivo but, unexpectedly, exhibited similar chromatin association as wild-type PRC2, indicating an uncoupling of PRC2 activity and recruitment. With genetic and chemical tools, we demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2Y646X oncogenic mutations. These results revealed critical implications for the regulation and biology of PRC2 and a vulnerability in tackling PRC2-addicted cancers.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | PRC2 EZH2 allosteric activation alpha-helical mimetics H3K27 methylation |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > polycomb group genes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Chromatin dynamics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein methylation > histone methylation |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL labs > Hammell M. lab |
| Depositing User: | Matt Covey |
| Date: | 3 May 2018 |
| Date Deposited: | 23 Apr 2018 19:19 |
| Last Modified: | 14 Jun 2018 19:21 |
| PMCID: | PMC5935545 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36534 |
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