RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2

Qi Zhang, Nicholas J. McKenzie, Robert Warneford-Thomson, Emma H. Gail, Sarena F. Flanigan, Brady M. Owen, Richard Lauman, Vitalina Levina, Benjamin A. Garcia, Ralf B. Schittenhelm, Roberto Bonasio, Chen Davidovich

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in multicellular organisms by marking repressed genes and chromatin domains. In addition to four core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during cellular differentiation and define two major holo-PRC2 complexes: PRC2.1 and PRC2.2. PRC2 binds to RNA, which inhibits its enzymatic activity, but the mechanism of RNA-mediated inhibition of holo-PRC2 is poorly understood. Here we present in vivo and in vitro protein-RNA interaction maps and identify an RNA-binding patch within the allosteric regulatory site of human and mouse PRC2, adjacent to the methyltransferase center. RNA-mediated inhibition of holo-PRC2 is relieved by allosteric activation of PRC2 by H3K27me3 and JARID2-K116me3 peptides. Both holo-PRC2.1 and holo-PRC2.2 bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2.

Original languageEnglish
Pages (from-to)237-247
Number of pages11
JournalNature Structural and Molecular Biology
Volume26
Issue number3
DOIs
Publication statusPublished - 4 Mar 2019

Keywords

  • enzyme mechanisms
  • histone post-translational modifications
  • mass spectrometry
  • methylases
  • RNA

Cite this

Zhang, Qi ; McKenzie, Nicholas J. ; Warneford-Thomson, Robert ; Gail, Emma H. ; Flanigan, Sarena F. ; Owen, Brady M. ; Lauman, Richard ; Levina, Vitalina ; Garcia, Benjamin A. ; Schittenhelm, Ralf B. ; Bonasio, Roberto ; Davidovich, Chen. / RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2. In: Nature Structural and Molecular Biology. 2019 ; Vol. 26, No. 3. pp. 237-247.
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abstract = "Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in multicellular organisms by marking repressed genes and chromatin domains. In addition to four core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during cellular differentiation and define two major holo-PRC2 complexes: PRC2.1 and PRC2.2. PRC2 binds to RNA, which inhibits its enzymatic activity, but the mechanism of RNA-mediated inhibition of holo-PRC2 is poorly understood. Here we present in vivo and in vitro protein-RNA interaction maps and identify an RNA-binding patch within the allosteric regulatory site of human and mouse PRC2, adjacent to the methyltransferase center. RNA-mediated inhibition of holo-PRC2 is relieved by allosteric activation of PRC2 by H3K27me3 and JARID2-K116me3 peptides. Both holo-PRC2.1 and holo-PRC2.2 bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2.",
keywords = "enzyme mechanisms, histone post-translational modifications, mass spectrometry, methylases, RNA",
author = "Qi Zhang and McKenzie, {Nicholas J.} and Robert Warneford-Thomson and Gail, {Emma H.} and Flanigan, {Sarena F.} and Owen, {Brady M.} and Richard Lauman and Vitalina Levina and Garcia, {Benjamin A.} and Schittenhelm, {Ralf B.} and Roberto Bonasio and Chen Davidovich",
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Zhang, Q, McKenzie, NJ, Warneford-Thomson, R, Gail, EH, Flanigan, SF, Owen, BM, Lauman, R, Levina, V, Garcia, BA, Schittenhelm, RB, Bonasio, R & Davidovich, C 2019, 'RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2' Nature Structural and Molecular Biology, vol. 26, no. 3, pp. 237-247. https://doi.org/10.1038/s41594-019-0197-y

RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2. / Zhang, Qi; McKenzie, Nicholas J.; Warneford-Thomson, Robert; Gail, Emma H.; Flanigan, Sarena F.; Owen, Brady M.; Lauman, Richard; Levina, Vitalina; Garcia, Benjamin A.; Schittenhelm, Ralf B.; Bonasio, Roberto; Davidovich, Chen.

In: Nature Structural and Molecular Biology, Vol. 26, No. 3, 04.03.2019, p. 237-247.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Warneford-Thomson, Robert

AU - Gail, Emma H.

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AU - Owen, Brady M.

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AB - Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in multicellular organisms by marking repressed genes and chromatin domains. In addition to four core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during cellular differentiation and define two major holo-PRC2 complexes: PRC2.1 and PRC2.2. PRC2 binds to RNA, which inhibits its enzymatic activity, but the mechanism of RNA-mediated inhibition of holo-PRC2 is poorly understood. Here we present in vivo and in vitro protein-RNA interaction maps and identify an RNA-binding patch within the allosteric regulatory site of human and mouse PRC2, adjacent to the methyltransferase center. RNA-mediated inhibition of holo-PRC2 is relieved by allosteric activation of PRC2 by H3K27me3 and JARID2-K116me3 peptides. Both holo-PRC2.1 and holo-PRC2.2 bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2.

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