Allosteric regulation of protein 14-3-3ζ scaffold by small-molecule editing modulates histone H3 post-translational modifications
| Autor: | Yan-Jun Wan, Xiao-Meng Shi, Yang Liu, Zhiyong Du, Xiao-Min Song, Li-Chao Wang, Kechun Liu, Xiao-Wen Zhang, Dan Liu, Ming-Bo Zhao, Liwen Han, Qing Xia, Yi Qian, Heng Yang, Yong Jiang, Li-Xi Liao, Peng-Fei Tu, Ke-Wu Zeng |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male DNA repair Allosteric regulation Medicine (miscellaneous) Methylation Cell Line 14-3-3ζ Histones Rats Sprague-Dawley 03 medical and health sciences Histone H3 Mice 0302 clinical medicine Allosteric Regulation Phenols Histone post-translational modifications Transcriptional regulation Autophagy Animals Humans Phosphorylation Pharmacology Toxicology and Pharmaceutics (miscellaneous) allosteric effect autophagy-lysosome function Mice Inbred BALB C biology Chemistry Acetylation Middle Aged Small molecule Cell biology Rats 030104 developmental biology Histone 14-3-3 Proteins Gene Expression Regulation Models Animal biology.protein endoplasmic reticulum stress Protein Multimerization Protein Processing Post-Translational 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Background: Histone post-translational modifications (PTMs) are involved in various biological processes such as transcriptional activation, chromosome packaging, and DNA repair. Previous studies mainly focused on PTMs by directly targeting histone-modifying enzymes such as HDACs and HATs. Methods and Results: In this study, we discovered a previously unexplored regulation mechanism for histone PTMs by targeting transcription regulation factor 14-3-3ζ. Mechanistic studies revealed 14-3-3ζ dimerization as a key prerequisite, which could be dynamically induced via an allosteric effect. The selective inhibition of 14-3-3ζ dimer interaction with histone H3 modulated histone H3 PTMs by exposing specific modification sites including acetylation, trimethylation, and phosphorylation, and reprogrammed gene transcription profiles for autophagy-lysosome function and endoplasmic reticulum stress. Conclusion: Our findings demonstrate the feasibility of editing histone PTM patterns by targeting transcription regulation factor 14-3-3ζ, and provide a distinctive PTM editing strategy which differs from current histone modification approaches. |
| Databáze: | OpenAIRE |
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