O -GlcNAcylation regulates the stability and enzymatic activity of the histone methyltransferase EZH2
| Autor: | Pei-Wen Lo, Chi-Huey Wong, Chung-Yi Wu, Chein-Hung Chen, Jiun-Jie Shie, Tsui-Ling Hsu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Multidisciplinary Methyltransferase Glycosylation biology Chemistry EZH2 macromolecular substances Methylation Biological Sciences Cell biology 03 medical and health sciences Histone H3 chemistry.chemical_compound 030104 developmental biology Histone methyltransferase Gene expression biology.protein PRC2 |
| Zdroj: | Proceedings of the National Academy of Sciences. 115:7302-7307 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Protein O-glycosylation by attachment of β-N-acetylglucosamine (GlcNAc) to the Ser or Thr residue is a major posttranslational glycosylation event and is often associated with protein folding, stability, and activity. The methylation of histone H3 at Lys-27 catalyzed by the methyltransferase EZH2 was known to suppress gene expression and cancer development, and we previously reported that the O-GlcNAcylation of EZH2 at S76 stabilized EZH2 and facilitated the formation of H3K27me3 to inhibit tumor suppression. In this study, we employed a fluorescence-based method of sugar labeling combined with mass spectrometry to investigate EZH2 glycosylation and identified five O-GlcNAcylation sites. We also find that mutation of one or more of the O-GlcNAcylation sites S73A, S76A, S84A, and T313A in the N-terminal region decreases the stability of EZH2, but does not affect its association with the PRC2 components SUZ12 and EED. Mutation of the C-terminal O-GlcNAcylation site (S729A) in the catalytic domain of EZH2 abolishes the di- and trimethylation activities, but not the monomethylation of H3K27, nor the integrity of the PRC2/EZH2 core complex. Our results show the effect of individual O-GlcNAcylation sites on the function of EZH2 and suggest an alternative approach to tumor suppression through selective inhibition of EZH2 O-GlcNAcylation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|