Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of deve...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (17), p.8295-8300 |
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| creator | Jani, Krupa S. Jain, Siddhant U. Ge, Eva J. Diehl, Katharine L. Lundgren, Stefan M. Müller, Manuel M. Lewis, Peter W. Muir, Tom W. |
| description | Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states. Despite their importance, the molecular details of how PRC2 “senses” H3K36 methylation are unclear. We demonstrate that PRC2 is activated in cis by the unmodified side chain of H3K36, and that this activation results in a fivefold increase in the k
cat of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome. |
| doi_str_mv | 10.1073/pnas.1819029116 |
| format | Article |
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cat of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1819029116</identifier><identifier>PMID: 30967505</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Binding Sites - genetics ; Biological Sciences ; Catalysis ; Crosslinking ; Crosstalk ; DNA methylation ; Enhancer of Zeste Homolog 2 Protein - chemistry ; Enhancer of Zeste Homolog 2 Protein - genetics ; Enhancer of Zeste Homolog 2 Protein - metabolism ; Enzymatic activity ; Gene silencing ; Histone H3 ; Histone methyltransferase ; Histones - chemistry ; Histones - metabolism ; Homology ; Humans ; Lysine ; Methylation ; Models, Molecular ; Mutation ; Polycomb group proteins ; Protein Binding ; Recombinant Proteins - chemistry ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Substrates ; Tumorigenesis</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2019-04, Vol.116 (17), p.8295-8300</ispartof><rights>Copyright National Academy of Sciences Apr 23, 2019</rights><rights>2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-cbe73071a4acac3ec10626052ed47de2cd4410428579bd793197932d068209da3</citedby><cites>FETCH-LOGICAL-c509t-cbe73071a4acac3ec10626052ed47de2cd4410428579bd793197932d068209da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26703505$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26703505$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30967505$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jani, Krupa S.</creatorcontrib><creatorcontrib>Jain, Siddhant U.</creatorcontrib><creatorcontrib>Ge, Eva J.</creatorcontrib><creatorcontrib>Diehl, Katharine L.</creatorcontrib><creatorcontrib>Lundgren, Stefan M.</creatorcontrib><creatorcontrib>Müller, Manuel M.</creatorcontrib><creatorcontrib>Lewis, Peter W.</creatorcontrib><creatorcontrib>Muir, Tom W.</creatorcontrib><title>Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states. Despite their importance, the molecular details of how PRC2 “senses” H3K36 methylation are unclear. We demonstrate that PRC2 is activated in cis by the unmodified side chain of H3K36, and that this activation results in a fivefold increase in the k
cat of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome.</description><subject>Binding Sites - genetics</subject><subject>Biological Sciences</subject><subject>Catalysis</subject><subject>Crosslinking</subject><subject>Crosstalk</subject><subject>DNA methylation</subject><subject>Enhancer of Zeste Homolog 2 Protein - chemistry</subject><subject>Enhancer of Zeste Homolog 2 Protein - genetics</subject><subject>Enhancer of Zeste Homolog 2 Protein - metabolism</subject><subject>Enzymatic activity</subject><subject>Gene silencing</subject><subject>Histone H3</subject><subject>Histone methyltransferase</subject><subject>Histones - chemistry</subject><subject>Histones - metabolism</subject><subject>Homology</subject><subject>Humans</subject><subject>Lysine</subject><subject>Methylation</subject><subject>Models, Molecular</subject><subject>Mutation</subject><subject>Polycomb group proteins</subject><subject>Protein Binding</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>Substrates</subject><subject>Tumorigenesis</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9rFDEcxYModq2ePSmBXrxM-00ySSYXQZbWFQotohcRQjbz3W7W2WSdZAr9782ydf1xSQ7v8328xyPkNYNzBlpc7KLL56xjBrhhTD0hMwaGNao18JTMALhuupa3J-RFzhsAMLKD5-REgFFagpyR74uQS4pIF4IWFwa6DLHP1NEphp8T0owxh3hHd8n_wEJDpJffFpyWRJ0v4d4VpGWN9PbznNMtlvXDUEYX8wpHl_ElebZyQ8ZXj_8p-Xp1-WW-aK5vPn6af7huvARTGr9ELUAz1zrvvEDPQHEFkmPf6h6579uWQcs7qc2y10YwUx_eg-o4mN6JU_L-4LubllvsPcYaYrC7MWzd-GCTC_ZfJYa1vUv3VrWd0kJVg3ePBmOqrXOx25A9DoOLmKZsOa_xFJdMVvTsP3STpjHWepWqmOyEEZW6OFB-TDmPuDqGYWD3y9n9cvbPcvXi7d8djvzvqSrw5gBs6mDjUedKg9jrvwCoEJ1U</recordid><startdate>20190423</startdate><enddate>20190423</enddate><creator>Jani, Krupa S.</creator><creator>Jain, Siddhant U.</creator><creator>Ge, Eva J.</creator><creator>Diehl, Katharine L.</creator><creator>Lundgren, Stefan M.</creator><creator>Müller, Manuel M.</creator><creator>Lewis, Peter W.</creator><creator>Muir, Tom W.</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190423</creationdate><title>Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase</title><author>Jani, Krupa S. ; 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Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states. Despite their importance, the molecular details of how PRC2 “senses” H3K36 methylation are unclear. We demonstrate that PRC2 is activated in cis by the unmodified side chain of H3K36, and that this activation results in a fivefold increase in the k
cat of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30967505</pmid><doi>10.1073/pnas.1819029116</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Binding Sites - genetics Biological Sciences Catalysis Crosslinking Crosstalk DNA methylation Enhancer of Zeste Homolog 2 Protein - chemistry Enhancer of Zeste Homolog 2 Protein - genetics Enhancer of Zeste Homolog 2 Protein - metabolism Enzymatic activity Gene silencing Histone H3 Histone methyltransferase Histones - chemistry Histones - metabolism Homology Humans Lysine Methylation Models, Molecular Mutation Polycomb group proteins Protein Binding Recombinant Proteins - chemistry Recombinant Proteins - genetics Recombinant Proteins - metabolism Substrates Tumorigenesis |
| title | Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase |
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