PRC2 methylates histones and DNA (Homo sapiens)

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7, 8, 10, 18, 19, 233-6, 9, 20...2, 11, 13-15131, 2, 12, 16, 21...nucleoplasmcytosolMe3K-28-H3F3A MTF2 JARID2 SUZ12 PHF1 JARID2 HIST1H3A SUZ12 DNMT1,3A,3BSUZ12 DNMT1,3A,3B:PRC2:ChromatinChromatinEED H3F3A HIST1H4 EED RBBP7 AEBP2 RBBP7 PHF1 RBBP7 PHF19 HIST1H3A PRC2 Core:ChromatinEZH2 PRC2:Chromatin(H3K27me3)DNMT1,3A,3B:PRC2:Chromatin (5-mC, H3K27me3)AdoMetH3F3A DNMT3B RBBP4 DNMT1 SUZ12 HIST2H3A AEBP2 HIST1H4 Me3K-28-HIST1H3A PRC2DNMT1 EED HIST1H4 Me3K-28-HIST1H3A HIST2H3A HIST1H3A AdoHcyMe3K-28-HIST2H3A PHF19 H3F3A DNMT3A EZH2 HIST1H3A DNMT3A HIST2H3A Me3K-28-HIST2H3A RBBP4 Me3K-28-H3F3A EED RBBP7 RBBP4 RBBP4 HIST1H4 EZH2 EED HIST1H4 SUZ12 PRC2:ChromatinEZH2 RBBP7 HIST1H4 MTF2 EZH2 AdoMetH3F3A DNMT3B RBBP4 AdoHcyHIST2H3A 8, 17, 27


Description

Polycomb group proteins are responsible for the heritable repression of genes during development (Lee et al. 2006, Ku et al. 2008, reviewed in Simon and Kingston 2009, Margueron and Reinberg 2011, Di Croce and Helin 2013). Two major families of Polycomb complexes exist: Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2). PRC1 and PRC2 each appear to comprise sets of distinct complexes that contain common core subunits and distinct accessory subunits (reviewed in Nayak et al. 2011). PRC2, through its component EZH2 or, in some complexes, EZH1 produces the initial molecular mark of repression, the trimethylation of lysine-27 of histone H3 (H3K27me3). How PRC2 is initially recruited to a locus remains unknown, however cytosine-guanine (CpG) motifs and transcripts have been suggested. Different mechanisms may be used at different loci. The trimethylated H3K27 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression. Source:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114960view16:48, 25 January 2021ReactomeTeamReactome version 75
113404view11:47, 2 November 2020ReactomeTeamReactome version 74
112607view15:58, 9 October 2020ReactomeTeamReactome version 73
101523view11:39, 1 November 2018ReactomeTeamreactome version 66
101059view21:21, 31 October 2018ReactomeTeamreactome version 65
100590view19:54, 31 October 2018ReactomeTeamreactome version 64
100139view16:40, 31 October 2018ReactomeTeamreactome version 63
99689view15:09, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93795view13:36, 16 August 2017ReactomeTeamreactome version 61
93332view11:20, 9 August 2017ReactomeTeamreactome version 61
88109view09:57, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86418view09:17, 11 July 2016ReactomeTeamreactome version 56
83256view10:33, 18 November 2015ReactomeTeamVersion54
81366view12:53, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AEBP2 ProteinQ6ZN18 (Uniprot-TrEMBL)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
ChromatinComplexR-HSA-3211736 (Reactome)
DNMT1 ProteinP26358 (Uniprot-TrEMBL)
DNMT1,3A,3B:PRC2:Chromatin (5-mC, H3K27me3)ComplexR-HSA-3211699 (Reactome) The Polycomb Repressor Complex 2 (PRC2) is able to interact with and recruit DNMT1, DNMT3a, and DNMT3b, all of which transfer a methyl group from S-adenosylmethionine to the 5 position of the cytosine ring.EZH2 is required for DNA methylation at PRC2 targets.
DNMT1,3A,3B:PRC2:ChromatinComplexR-HSA-212288 (Reactome) The Polycomb Repressor Complex 2 (PRC2) is able to interact with and recruit DNMT1, DNMT3a, and DNMT3b, all of which transfer a methyl group from S-adenosylmethionine to the 5 position of the cytosine ring.EZH2 is required for DNA methylation at PRC2 targets.
DNMT1,3A,3BR-HSA-212315 (Reactome)
DNMT3A ProteinQ9Y6K1 (Uniprot-TrEMBL)
DNMT3B ProteinQ9UBC3 (Uniprot-TrEMBL)
EED ProteinO75530 (Uniprot-TrEMBL)
EZH2 ProteinQ15910 (Uniprot-TrEMBL)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
JARID2 ProteinQ92833 (Uniprot-TrEMBL)
MTF2 ProteinQ9Y483 (Uniprot-TrEMBL)
Me3K-28-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me3K-28-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Me3K-28-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
PHF1 ProteinO43189 (Uniprot-TrEMBL)
PHF19 ProteinQ5T6S3 (Uniprot-TrEMBL)
PRC2 Core:ChromatinComplexR-HSA-5084071 (Reactome)
PRC2:Chromatin (H3K27me3)ComplexR-HSA-3211731 (Reactome)
PRC2:ChromatinComplexR-HSA-3211709 (Reactome)
PRC2R-HSA-5084084 (Reactome)
RBBP4 ProteinQ09028 (Uniprot-TrEMBL)
RBBP7 ProteinQ16576 (Uniprot-TrEMBL)
SUZ12 ProteinQ15022 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-212263 (Reactome)
AdoHcyArrowR-HSA-212269 (Reactome)
AdoMetR-HSA-212263 (Reactome)
AdoMetR-HSA-212269 (Reactome)
ChromatinR-HSA-212252 (Reactome)
DNMT1,3A,3B:PRC2:Chromatin (5-mC, H3K27me3)ArrowR-HSA-212269 (Reactome)
DNMT1,3A,3B:PRC2:ChromatinArrowR-HSA-212222 (Reactome)
DNMT1,3A,3B:PRC2:ChromatinR-HSA-212269 (Reactome)
DNMT1,3A,3B:PRC2:Chromatinmim-catalysisR-HSA-212269 (Reactome)
DNMT1,3A,3BR-HSA-212222 (Reactome)
PRC2 Core:ChromatinR-HSA-212222 (Reactome)
PRC2:Chromatin (H3K27me3)ArrowR-HSA-212263 (Reactome)
PRC2:ChromatinArrowR-HSA-212252 (Reactome)
PRC2:ChromatinR-HSA-212263 (Reactome)
PRC2:Chromatinmim-catalysisR-HSA-212263 (Reactome)
PRC2R-HSA-212252 (Reactome)
R-HSA-212222 (Reactome) In tumor cells the Polycomb Repressor Complex 2 associates with a DNA methyltransferase (DNMT) via the N-terminal region of EZH2 (Vire et al. 2006). DNMT1, DNMT3a, and DNMT3b can each bind EZH2 though only one is bound at any time. As inferred from mouse (Rush et al. 2009), EZH2 tethered to a locus is able to recruit Dnmt3a but additional factors may be required to trigger de novo DNA methylation. It is unknown if the DNMT is recruited only after PRC2 has been targeted to a locus.
R-HSA-212252 (Reactome) The core of the Polycomb Repressor Complex 2 (PRC2) contains EZH2, EED, SUV12, RpAp46, and RpAp48 (Kuzzmichev et al. 2002, Cao et al. 2002). PRC2 complexes at different sites in the genome contain the core subunits plus different accessory subunits. In Drosophila PRC2 is recruited to chromatin by specific DNA sequences. In vertebrates PRC2 appears to be recruited to chromatin through several mechanisms: some (about 20%) of noncoding RNAs tethered to the locus of origin recruit PRC2 via the RNA-binding activity of EZH2 (Zhao et al. 2008, Khalil et al. 2009), GC-rich sequence elements in DNA (Mendenhall et al. 2010) and poly(ADP-ribosyl) polymerase at sites of DNA damage (Chou et al. 2010) can also recruit polycomb components, The DNA-binding proteins JARID2, AEBP2, and YY1 recruit PRC2 (Pasini et al. 2010, Li et al. 2010, reviewed in Kim and Kim 2012). The EED subunit of PRC2 can bind existing trimethylated lysine-27 on histone H3 of PRC2 which may provide a mechanism for propagation of trimethylated lysine-27 during DNA replication (Xu et al. 2010).
R-HSA-212263 (Reactome) EZH2 , a SET domain protein, trimethylates histone H3 at lysine 27 (H3K27) and lysine 9 (H3K9) (Kuzmichev et al. 2002, Cao et al. 2002, Kuzmichev et al. 2004, Martin et al. 2006, McCabe et al. 2012, Swalm et al. 2013). EZH2 has greater activity with lysine residues that have fewer methyl groups (unmethylated:monomethylated:dimethylated=9:6:1, McCabe et al. 2012). EZH1 rather than EZH2 is present in some PRC2 complexes and can also catalyze the trimethylation of H3K27 (inferred from mouse in Shen et al. 2008), however EZH1 is also able to repress transcription without methylating histone H3 (Margueron et al. 2008).
R-HSA-212269 (Reactome) DNA methyltransferases (DNMTs) associate with EZH2 of the Polycomb Repressive Complex 2 (PRC2) and methylate the 5 position of the cytosine ring in DNA (Vire et al. 2006). The histone methyltransferase activity of EZH2 also trimethylates lysine-27 of histone H3 (H3K27me3). The promoters of the MYT, WNT1, KCNA1, and CNR1 genes are methylated on cytosine by the DNMT:PRC2 complex however not all loci that have H3K27me3 by PRC2 also have cytosine methylation (Vire et al. 2006, Brinkman et al. 2012). DNA methylation and H3K27me3 appear to be mutually exclusive in CpG islands but are compatible throughout most of the rest of the genome (Brinkman et al. 2012). In mouse, DNA methylation and H3K27me3 appear to be antagonistic at most loci: loss of DNA methylation causes increased H3K27me3 while loss of PRC2 has little effect on DNA methylation (Hagarman et al. 2013). By competing with DNMT3a,b for association with PRC2, DNMT3L may antagonize DNA methylation at sites bound by PRC2 (Neri et al. 2013).
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