Structural basis for inactivation of PRC2 by G-quadruplex RNA

• DOI: 10.1126/science.adh0059
• Publication Date: 2023-09-21T17:59:47Z
• Authors: Jiarui Song; Anne R. Gooding; Wayne O. Hemphill; Brittney D. Love; Anne Robertson; Liqi Yao; Leonard I. Zon; Trista E. North; Vignesh Kasinath; Thomas R. Cech
• Keywords: Protein Conformation; Cryoelectron Microscopy; Polycomb Repressive Complex 2; Crystallography, X-Ray; Article; Histones; G-Quadruplexes; Gain of Function Mutation; RNA Precursors; Animals; RNA, Long Noncoding; Enhancer of Zeste Homolog 2 Protein; Protein Multimerization; Promoter Regions, Genetic; Zebrafish; Protein Binding

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.