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PreprintCited by 73Epigenetics and DNA MethylationGenomics and Chromatin DynamicsDNA and Nucleic Acid Chemistry

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Structural basis for inactivation of PRC2 by G-quadruplex RNA

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Song, Jiarui, Gooding, Anne R., Hemphill, Wayne O., Kasinath, Vignesh, Cech, Thomas R.·2023·Science
DOI 10.1101/2023.02.06.527314PMC PMC11191771

Preprint — published as 10.1126/science.adh0059 · Paper page

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Abstract

The histone methyltransferase PRC2 (Polycomb Repressive Complex 2) silences genes via successively attaching three methyl groups to lysine 27 of histone H3. PRC2 associates with numerous pre-mRNA and lncRNA transcripts with a binding preference for G-quadruplex RNA. Here, we present a 3.3Å-resolution cryo-EM structure of PRC2 bound to a G-quadruplex RNA. Notably, RNA mediates the dimerization of PRC2 by binding both protomers and inducing a protein interface comprised of two copies of the catalytic subunit EZH2, which limits nucleosome DNA interaction and occludes H3 tail accessibility to the active site. Our results reveal an unexpected mechanism for RNA-mediated inactivation of a chromatin-modifying enzyme. Furthermore, the flexible loop of EZH2 that helps stabilize RNA binding also facilitates the handoff between RNA and DNA, an activity implicated in PRC2 regulation by RNA. One-Sentence Summary: Cryo-EM structure of RNA-bound PRC2 dimer elucidates an unexpected mechanism of PRC2 inhibition by RNA.

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Metadata

Authors
Song, J., Gooding, A. R., Hemphill, W. O., Kasinath, V., & Cech, T. R.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of Colorado Boulder (US)
Corresponding author
  • Kasinath, Vignesh
  • Cech, Thomas R.
ORCID
Venue
Science
Publisher
openRxiv
Published
2023-02-06
Volume
381
Issue
6664
Pages
1331-1337
ISSN
0036-8075 (ISSN-L)
DOI
10.1101/2023.02.06.527314
PMC
PMC11191771
OpenAlex
W4386917171
Cited by
73
References
1
Citations by year
2026: 14 · 2025: 21 · 2024: 34 · 2023: 4
FWCI
6.50
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • PubMed Central (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Ministry of Education, India
  • National Institutes of Health (SCR_018986)
  • Weill Cornell Medical College
  • University of Colorado Boulder
  • National Heart, Lung, and Blood Institute (R01HL144780)
  • National Institute of General Medical Sciences (R00GM132544, F32GM147934, R35GM155426)
  • National Institute of Diabetes and Digestive and Kidney Diseases (RC2DK120535)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
polycomb repressive complex 2, RNA G-quadruplex, EZH2, H3K27me3, nucleosome-DNA interactions, long non-coding RNA, pre-mRNA, chromatin regulation, gain-of-function mutations, zebrafish

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