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The macromolecular complexes of histones affect protein arginine methyltransferase activities

Histone arginine methylation is a key post-translational modification that mediates epigenetic events that activate or repress gene transcription. Protein arginine methyltransferases (PRMTs) are the driving force for the process of arginine methylation, and the core histone proteins have been shown...

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Autores principales: Fulton, Melody D., Cao, Mengtong, Ho, Meng-Chiao, Zhao, Xinyang, Zheng, Y. George
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511957/
https://www.ncbi.nlm.nih.gov/pubmed/34492270
http://dx.doi.org/10.1016/j.jbc.2021.101123
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author Fulton, Melody D.
Cao, Mengtong
Ho, Meng-Chiao
Zhao, Xinyang
Zheng, Y. George
author_facet Fulton, Melody D.
Cao, Mengtong
Ho, Meng-Chiao
Zhao, Xinyang
Zheng, Y. George
author_sort Fulton, Melody D.
collection PubMed
description Histone arginine methylation is a key post-translational modification that mediates epigenetic events that activate or repress gene transcription. Protein arginine methyltransferases (PRMTs) are the driving force for the process of arginine methylation, and the core histone proteins have been shown to be substrates for most PRMT family members. However, previous reports of the enzymatic activities of PRMTs on histones in the context of nucleosomes seem contradictory. Moreover, what governs nucleosomal substrate recognition of different PRMT members is not understood. We sought to address this key biological question by examining how different macromolecular contexts where the core histones reside may regulate arginine methylation catalyzed by individual PRMT members (i.e., PRMT1, PRMT3, PRMT4, PRMT5, PRMT6, PRMT7, and PRMT8). Our results demonstrated that the substrate context exhibits a huge impact on the histone arginine methylation activity of PRMTs. Although all the tested PRMTs methylate multiple free histones individually, they show a preference for one particular histone substrate in the context of the histone octamer. We found that PRMT1, PRMT3, PRMT5, PRMT6, PRMT7, and PRMT8 preferentially methylate histone H4, whereas PRMT4/coactivator-associated arginine methyltransferase 1 prefers histone H3. Importantly, neither reconstituted nor cell-extracted mononucleosomes could be methylated by any PRMTs tested. Structural analysis suggested that the electrostatic interaction may play a mechanistic role in priming the substrates for methylation by PRMT enzymes. Taken together, this work expands our knowledge on the molecular mechanisms of PRMT substrate recognition and has important implications for understanding cellular dynamics and kinetics of histone arginine methylation in regulating gene transcription and other chromatin-templated processes.
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spelling pubmed-85119572021-10-21 The macromolecular complexes of histones affect protein arginine methyltransferase activities Fulton, Melody D. Cao, Mengtong Ho, Meng-Chiao Zhao, Xinyang Zheng, Y. George J Biol Chem Research Article Histone arginine methylation is a key post-translational modification that mediates epigenetic events that activate or repress gene transcription. Protein arginine methyltransferases (PRMTs) are the driving force for the process of arginine methylation, and the core histone proteins have been shown to be substrates for most PRMT family members. However, previous reports of the enzymatic activities of PRMTs on histones in the context of nucleosomes seem contradictory. Moreover, what governs nucleosomal substrate recognition of different PRMT members is not understood. We sought to address this key biological question by examining how different macromolecular contexts where the core histones reside may regulate arginine methylation catalyzed by individual PRMT members (i.e., PRMT1, PRMT3, PRMT4, PRMT5, PRMT6, PRMT7, and PRMT8). Our results demonstrated that the substrate context exhibits a huge impact on the histone arginine methylation activity of PRMTs. Although all the tested PRMTs methylate multiple free histones individually, they show a preference for one particular histone substrate in the context of the histone octamer. We found that PRMT1, PRMT3, PRMT5, PRMT6, PRMT7, and PRMT8 preferentially methylate histone H4, whereas PRMT4/coactivator-associated arginine methyltransferase 1 prefers histone H3. Importantly, neither reconstituted nor cell-extracted mononucleosomes could be methylated by any PRMTs tested. Structural analysis suggested that the electrostatic interaction may play a mechanistic role in priming the substrates for methylation by PRMT enzymes. Taken together, this work expands our knowledge on the molecular mechanisms of PRMT substrate recognition and has important implications for understanding cellular dynamics and kinetics of histone arginine methylation in regulating gene transcription and other chromatin-templated processes. American Society for Biochemistry and Molecular Biology 2021-09-06 /pmc/articles/PMC8511957/ /pubmed/34492270 http://dx.doi.org/10.1016/j.jbc.2021.101123 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Fulton, Melody D.
Cao, Mengtong
Ho, Meng-Chiao
Zhao, Xinyang
Zheng, Y. George
The macromolecular complexes of histones affect protein arginine methyltransferase activities
title The macromolecular complexes of histones affect protein arginine methyltransferase activities
title_full The macromolecular complexes of histones affect protein arginine methyltransferase activities
title_fullStr The macromolecular complexes of histones affect protein arginine methyltransferase activities
title_full_unstemmed The macromolecular complexes of histones affect protein arginine methyltransferase activities
title_short The macromolecular complexes of histones affect protein arginine methyltransferase activities
title_sort macromolecular complexes of histones affect protein arginine methyltransferase activities
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511957/
https://www.ncbi.nlm.nih.gov/pubmed/34492270
http://dx.doi.org/10.1016/j.jbc.2021.101123
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