Activation of automethylated PRC2 by dimerization on chromatin

被引：1

作者：

Sauer, Paul V. ^{[1
,2
]}

Pavlenko, Egor ^{[3
,4
]}

Cookis, Trinity ^{[5
]}

Zirden, Linda C. ^{[3
,4
]}

Renn, Juliane ^{[3
,4
]}

Singhal, Ankush ^{[6
]}

Hunold, Pascal ^{[3
,4
,7
]}

Hoehne-Wiechmann, Michaela N. ^{[3
,4
,7
]}

van Ray, Olivia ^{[3
,4
,7
]}

Kaschani, Farnusch ^{[8
]}

Kaiser, Markus ^{[8
]}

Haensel-Hertsch, Robert ^{[3
,4
,7
,9
,10
]}

Sanbonmatsu, Karissa Y. ^{[6
]}

Nogales, Eva ^{[1
,2
,5
,11
]}

Poepsel, Simon ^{[3
,4
,10
]}

机构：

[1] Univ Calif Berkeley, Calif Inst Quantitat Biosci QB3, Berkeley, CA 94720 USA

[2] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA

[3] Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany

[4] Univ Hosp, Univ Cologne, D-50931 Cologne, Germany

[5] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA

[6] Los Alamos Natl Lab, Theoret Div, Theoret Biol & Biophys, Los Alamos, NM 87545 USA

[7] Univ Cologne, Fac Med, Dept Translat Genom, D-50931 Cologne, Germany

[8] Univ Duisburg Essen, Fac Biol, Ctr Med Biotechnol ZMB, Dept Chem Biol, Essen, Germany

[9] Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany

[10] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respons, D-50931 Cologne, Germany

[11] Lawrence Berkeley Natl Lab, Mol Biophys & Integrat Bioimaging Div, Berkeley, CA 94720 USA

来源：

MOLECULAR CELL | 2024年 / 84卷 / 20期

基金：

美国国家科学基金会;

关键词：

MOLECULAR-DYNAMICS; PROTEIN; NUCLEOSOME; COMPLEX; METHYLATION; ALGORITHMS; ENRICHMENT; INHIBITOR; BINDING; JARID2;

D O I：

10.1016/j.molcel.2024.08.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a previously unknown mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification- coupled dimerization in the regulation of chromatin-modifying complexes.

引用

页码：3885 / 3898

页数：14

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