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Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas
EZH2, the catalytic subunit of the PRC2 complex, catalyzes the mono- through trimethylation of lysine 27 on histone H3 (H3K27). Histone H3K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. Point mutations of the EZ...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2010-12, Vol.107 (49), p.20980-20985 |
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| container_issue | 49 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Sneeringer, Christopher J. Scott, Margaret Porter Kuntz, Kevin W. Knutson, Sarah K. Pollock, Roy M. Richon, Victoria M. Copeland, Robert A. Wells, James A. |
| description | EZH2, the catalytic subunit of the PRC2 complex, catalyzes the mono- through trimethylation of lysine 27 on histone H3 (H3K27). Histone H3K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. Point mutations of the EZH2 gene (Tyr641) have been reported to be linked to subsets of human B-cell lymphoma. The mutant allele is always found associated with a wild-type allele (heterozygous) in disease cells, and the mutations were reported to ablate the enzymatic activity of the PRC2 complex for methylating an unmodified peptide substrate. Here we demonstrate that the WT enzyme displays greatest catalytic efficiency (k cat /K) for the zero to monomethylation reaction of H3K27 and diminished efficiency for subsequent (mono- to di- and di- to trimethylation) reactions. In stark contrast, the disease-associated Y641 mutations display very limited ability to perform the first methylation reaction, but have enhanced catalytic efficiency for the subsequent reactions, relative to the WT enzyme. These results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZH1) together with the mutant PRC2s for augmented conversion of H3K27 to the trimethylated form. To our knowledge, this is the first example of a human disease that is dependent on the coordinated activities of normal and disease-associated mutant enzymatic function. |
| doi_str_mv | 10.1073/pnas.1012525107 |
| format | article |
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Histone H3K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. Point mutations of the EZH2 gene (Tyr641) have been reported to be linked to subsets of human B-cell lymphoma. The mutant allele is always found associated with a wild-type allele (heterozygous) in disease cells, and the mutations were reported to ablate the enzymatic activity of the PRC2 complex for methylating an unmodified peptide substrate. Here we demonstrate that the WT enzyme displays greatest catalytic efficiency (k cat /K) for the zero to monomethylation reaction of H3K27 and diminished efficiency for subsequent (mono- to di- and di- to trimethylation) reactions. In stark contrast, the disease-associated Y641 mutations display very limited ability to perform the first methylation reaction, but have enhanced catalytic efficiency for the subsequent reactions, relative to the WT enzyme. These results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZH1) together with the mutant PRC2s for augmented conversion of H3K27 to the trimethylated form. To our knowledge, this is the first example of a human disease that is dependent on the coordinated activities of normal and disease-associated mutant enzymatic function.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1012525107</identifier><identifier>PMID: 21078963</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>B cell lymphoma ; Biological Sciences ; Catalysis ; Cell lines ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Enhancer of Zeste Homolog 2 Protein ; Enzyme substrates ; Enzymes ; Genes ; Genetic mutation ; Histones ; Histones - metabolism ; Humans ; Kinetics ; Lymphoma, B-Cell - enzymology ; Lymphoma, B-Cell - etiology ; Lymphoma, B-Cell - genetics ; Lysine - metabolism ; Methylation ; Nucleosomes ; Point Mutation ; Polycomb Repressive Complex 2 ; Stem cells ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-12, Vol.107 (49), p.20980-20985</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c569t-3050439c56cd46f1c02a114e3285284604da21bd638d5526d288ced919e401ad3</citedby><cites>FETCH-LOGICAL-c569t-3050439c56cd46f1c02a114e3285284604da21bd638d5526d288ced919e401ad3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/49.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25756818$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25756818$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829,58593,58826</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21078963$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sneeringer, Christopher J.</creatorcontrib><creatorcontrib>Scott, Margaret Porter</creatorcontrib><creatorcontrib>Kuntz, Kevin W.</creatorcontrib><creatorcontrib>Knutson, Sarah K.</creatorcontrib><creatorcontrib>Pollock, Roy M.</creatorcontrib><creatorcontrib>Richon, Victoria M.</creatorcontrib><creatorcontrib>Copeland, Robert A.</creatorcontrib><creatorcontrib>Wells, James A.</creatorcontrib><title>Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>EZH2, the catalytic subunit of the PRC2 complex, catalyzes the mono- through trimethylation of lysine 27 on histone H3 (H3K27). Histone H3K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. Point mutations of the EZH2 gene (Tyr641) have been reported to be linked to subsets of human B-cell lymphoma. The mutant allele is always found associated with a wild-type allele (heterozygous) in disease cells, and the mutations were reported to ablate the enzymatic activity of the PRC2 complex for methylating an unmodified peptide substrate. Here we demonstrate that the WT enzyme displays greatest catalytic efficiency (k cat /K) for the zero to monomethylation reaction of H3K27 and diminished efficiency for subsequent (mono- to di- and di- to trimethylation) reactions. In stark contrast, the disease-associated Y641 mutations display very limited ability to perform the first methylation reaction, but have enhanced catalytic efficiency for the subsequent reactions, relative to the WT enzyme. These results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZH1) together with the mutant PRC2s for augmented conversion of H3K27 to the trimethylated form. To our knowledge, this is the first example of a human disease that is dependent on the coordinated activities of normal and disease-associated mutant enzymatic function.</description><subject>B cell lymphoma</subject><subject>Biological Sciences</subject><subject>Catalysis</subject><subject>Cell lines</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enhancer of Zeste Homolog 2 Protein</subject><subject>Enzyme substrates</subject><subject>Enzymes</subject><subject>Genes</subject><subject>Genetic mutation</subject><subject>Histones</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Lymphoma, B-Cell - enzymology</subject><subject>Lymphoma, B-Cell - etiology</subject><subject>Lymphoma, B-Cell - genetics</subject><subject>Lysine - metabolism</subject><subject>Methylation</subject><subject>Nucleosomes</subject><subject>Point Mutation</subject><subject>Polycomb Repressive Complex 2</subject><subject>Stem cells</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><recordid>eNqFkk2PFCEQhonRuOPq2ZOGm3pol88GLiY6WR3jJl704oWwwNhsupsW6DHzX_yx0s64o6c9QRVPvVDFC8BTjF5jJOjFNJpcd5hwwmviHlhhpHDTMoXugxVCRDSSEXYGHuV8gxBSXKKH4IxUVqqWrsCvdYzJhdEU76CxJexCCT7DuIU_Q--asp88nPo5w2EuZizw8tuGQJfCzsMyDzE1Judow5_6rsKppDD40u17U0IcF6F-n8PoIRGwxl3IJdZoQ-HLDf1ExCsYanYezAjfNdb3feWHqYuDyY_Bg63ps39yXM_B1_eXX9ab5urzh4_rt1eN5a0qDUUcMapqYB1rt9giYjBmnhLJiWQtYs4QfO1aKh3npHVESuudwsozhI2j5-DNQXearwfvrB9LMr2eaicm7XU0Qf9_MoZOf487TetIiRJV4MVRIMUfs89FDyEvvZjRxzlrhQRmUtWJ30XK-nUcC8HvJnErFMUCVfLiQNoUc05-e_tyjPRiE73YRJ9sUiue_9vwLf_XFxWAR2CpPMkJzZQmSMnl1mcH5KZ-aDpJcMFbiSX9DZkjzfU</recordid><startdate>20101207</startdate><enddate>20101207</enddate><creator>Sneeringer, Christopher J.</creator><creator>Scott, Margaret Porter</creator><creator>Kuntz, Kevin W.</creator><creator>Knutson, Sarah K.</creator><creator>Pollock, Roy M.</creator><creator>Richon, Victoria M.</creator><creator>Copeland, Robert A.</creator><creator>Wells, James A.</creator><general>National Academy of Sciences</general><general>National Acad 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>7X8</scope><scope>7T5</scope><scope>7TM</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20101207</creationdate><title>Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas</title><author>Sneeringer, Christopher J. ; Scott, Margaret Porter ; Kuntz, Kevin W. ; Knutson, Sarah K. ; Pollock, Roy M. ; Richon, Victoria M. ; Copeland, Robert A. ; Wells, James A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c569t-3050439c56cd46f1c02a114e3285284604da21bd638d5526d288ced919e401ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>B cell lymphoma</topic><topic>Biological Sciences</topic><topic>Catalysis</topic><topic>Cell lines</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enhancer of Zeste Homolog 2 Protein</topic><topic>Enzyme substrates</topic><topic>Enzymes</topic><topic>Genes</topic><topic>Genetic mutation</topic><topic>Histones</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Lymphoma, B-Cell - enzymology</topic><topic>Lymphoma, B-Cell - etiology</topic><topic>Lymphoma, B-Cell - genetics</topic><topic>Lysine - metabolism</topic><topic>Methylation</topic><topic>Nucleosomes</topic><topic>Point Mutation</topic><topic>Polycomb Repressive Complex 2</topic><topic>Stem cells</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sneeringer, Christopher J.</creatorcontrib><creatorcontrib>Scott, Margaret Porter</creatorcontrib><creatorcontrib>Kuntz, Kevin W.</creatorcontrib><creatorcontrib>Knutson, Sarah K.</creatorcontrib><creatorcontrib>Pollock, Roy M.</creatorcontrib><creatorcontrib>Richon, Victoria M.</creatorcontrib><creatorcontrib>Copeland, Robert A.</creatorcontrib><creatorcontrib>Wells, James A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sneeringer, Christopher J.</au><au>Scott, Margaret Porter</au><au>Kuntz, Kevin W.</au><au>Knutson, Sarah K.</au><au>Pollock, Roy M.</au><au>Richon, Victoria M.</au><au>Copeland, Robert A.</au><au>Wells, James A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2010-12-07</date><risdate>2010</risdate><volume>107</volume><issue>49</issue><spage>20980</spage><epage>20985</epage><pages>20980-20985</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>ObjectType-Article-2</notes><notes>ObjectType-Feature-1</notes><notes>1C.J.S. and M.P.S. contributed equally to this work.</notes><notes>Edited by James A. Wells, University of California, San Francisco, CA, and approved October 19, 2010 (received for review August 24, 2010)</notes><notes>Author contributions: M.P.S., R.M.P., V.M.R., and R.A.C. designed research; C.J.S. and S.K.K. performed research; C.J.S., M.P.S., K.W.K., S.K.K., R.M.P., and R.A.C. analyzed data; and M.P.S., K.W.K., V.M.R., and R.A.C. wrote the paper.</notes><abstract>EZH2, the catalytic subunit of the PRC2 complex, catalyzes the mono- through trimethylation of lysine 27 on histone H3 (H3K27). Histone H3K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. Point mutations of the EZH2 gene (Tyr641) have been reported to be linked to subsets of human B-cell lymphoma. The mutant allele is always found associated with a wild-type allele (heterozygous) in disease cells, and the mutations were reported to ablate the enzymatic activity of the PRC2 complex for methylating an unmodified peptide substrate. Here we demonstrate that the WT enzyme displays greatest catalytic efficiency (k cat /K) for the zero to monomethylation reaction of H3K27 and diminished efficiency for subsequent (mono- to di- and di- to trimethylation) reactions. In stark contrast, the disease-associated Y641 mutations display very limited ability to perform the first methylation reaction, but have enhanced catalytic efficiency for the subsequent reactions, relative to the WT enzyme. These results imply that the malignant phenotype of disease requires the combined activities of a H3K27 monomethylating enzyme (PRC2 containing WT EZH2 or EZH1) together with the mutant PRC2s for augmented conversion of H3K27 to the trimethylated form. To our knowledge, this is the first example of a human disease that is dependent on the coordinated activities of normal and disease-associated mutant enzymatic function.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21078963</pmid><doi>10.1073/pnas.1012525107</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | B cell lymphoma Biological Sciences Catalysis Cell lines DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Enhancer of Zeste Homolog 2 Protein Enzyme substrates Enzymes Genes Genetic mutation Histones Histones - metabolism Humans Kinetics Lymphoma, B-Cell - enzymology Lymphoma, B-Cell - etiology Lymphoma, B-Cell - genetics Lysine - metabolism Methylation Nucleosomes Point Mutation Polycomb Repressive Complex 2 Stem cells Transcription Factors - genetics Transcription Factors - metabolism |
| title | Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas |
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