Structural basis for inactivation of PRC2 by G-quadruplex RNA
Open accessPublished version of a preprint
Abstract
Polycomb repressive complex 2 (PRC2) silences genes through trimethylation of histone H3K27. PRC2 associates with numerous precursor messenger RNAs (pre-mRNAs) and long noncoding RNAs (lncRNAs) with a binding preference for G-quadruplex RNA. In this work, we present a 3.3-Å-resolution cryo–electron microscopy 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 composed of two copies of the catalytic subunit EZH2, thereby blocking nucleosome DNA interaction and histone H3 tail accessibility. Furthermore, an RNA-binding loop of EZH2 facilitates the handoff between RNA and DNA, another activity implicated in PRC2 regulation by RNA. We identified a gain-of-function mutation in this loop that activates PRC2 in zebrafish. Our results reveal mechanisms for RNA-mediated regulation of a chromatin-modifying enzyme.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
The Polycomb complex PRC2 and its mark in life
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Molecular mechanisms directing PRC2 recruitment and H3K27 methylation
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- Authors
- Song, J., Gooding, A. R., Hemphill, W. O., Love, B. D., Robertson, A., Yao, L., Zon, L. I., North, T. E., Kasinath, V., & Cech, T. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Boston Children's Hospital (US)
- University of Colorado Boulder (US)
- Corresponding author
- Kasinath, Vignesh
- Cech, Thomas R.
- ORCID
- Venue
- Science
- Published
- 2023-09-22
- Volume
- 381
- Issue
- 6664
- Pages
- 1331-1337
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC11191771
- OpenAlex
- W4386917171
- Cited by
- 73
- References
- 4
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 34 · 2023: 4
- FWCI
- 6.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- 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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