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Structural basis for inactivation of PRC2 by G-quadruplex RNA.

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.

SUBMITTER: Song J

PROVIDER: S-EPMC11191771 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Structural basis for inactivation of PRC2 by G-quadruplex RNA.

Song Jiarui J Gooding Anne R AR Hemphill Wayne O WO Love Brittney D BD Robertson Anne A Yao Liqi L Zon Leonard I LI North Trista E TE Kasinath Vignesh V Cech Thomas R TR

Science (New York, N.Y.) 20230921 6664

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 cataly ...[more]

PMID: 37733873

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