Structural basis for inactivation of PRC2 by G-quadruplex RNA

作者：Jiarui Song, Anne R. Gooding, Wayne O. Hemphill, Brittney Love, Anne L. Robertson, Liqi Yao, Leonard I. Zon, Trista E. North, Vignesh Kasinath, Thomas R. Cech · 发表于：Science · 年份：2023 · DOI：10.1126/science.adh0059 · 被引用次数：71 · 研究领域：RNA modifications and cancer、RNA Research and Splicing、Genomics and Chromatin Dynamics

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.