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Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2.

ABSTRACT: Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 trimethylation (H3K27me3), a hallmark of gene silencing. Here we report the crystal structures of an active PRC2 complex of 170 kilodaltons from the yeast Chaetomium thermophilum in both basal and stimulated states, which contain Ezh2, Eed, and the VEFS domain of Suz12 and are bound to a cancer-associated inhibiting H3K27M peptide and a S-adenosyl-l-homocysteine cofactor. The stimulated complex also contains an additional stimulating H3K27me3 peptide. Eed is engulfed by a belt-like structure of Ezh2, and Suz12(VEFS) contacts both of these two subunits to confer an unusual split active SET domain for catalysis. Comparison of PRC2 in the basal and stimulated states reveals a mobile Ezh2 motif that responds to stimulation to allosterically regulate the active site.

SUBMITTER: Jiao L

PROVIDER: S-EPMC5220110 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2.

Jiao Lianying L Liu Xin X

Science (New York, N.Y.) 20151015 6258

Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 trimethylation (H3K27me3), a hallmark of gene silencing. Here we report the crystal structures of an active PRC2 complex of 170 kilodaltons from the yeast Chaetomium thermophilum in both basal and stimulated states, which contain Ezh2, Eed, and the VEFS domain of Suz12 and are bound to a cancer-associated inhibiting H3K27M peptide and a S-adenosyl-l-homocysteine cofactor. The stimulated complex also contains an additional stimulating H ...[more]

PMID: 26472914

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Response to Comment on "Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2".

Project description:Zhang et al suggested that in the crystal structure of a polycomb repressive complex 2 from Chaetomium thermophilum (ctPRC2), a flexible linker region, but not the H3K27M cancer mutant peptide, better fits the electron density. Based on our new data, we agree with this alternative interpretation and provide the crystal structure of ctPRC2 bound to a bona fide H3K27M sequence.

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Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.

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Inhibition of Polycomb Repressive Complex 2 activity reduces trimethylation of H3K27 and affects development in Arabidopsis seedlings.

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Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.

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| S-EPMC10411902 | biostudies-literature

Polycomb repressive complex 1 modifies transcription of active genes.

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| S-EPMC5540264 | biostudies-literature

Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.

Project description:Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of flowering time in plants. In Drosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs 1-4). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes. Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repression in vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.

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| S-EPMC10284349 | biostudies-literature

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