The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)
Open accessAbstract
Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive posttranslational modification mediated by the histone methyltransferase EZH2. EZH2 is a component of the polycomb repressive complex 2 and is overexpressed in many cancers. In B-cell lymphomas, its substrate preference is frequently altered through somatic mutation of the EZH2 Y641 residue. Herein, we identify mutation of EZH2 A677 to a glycine (A677G) among lymphoma cell lines and primary tumor specimens. Similar to Y641 mutant cell lines, an A677G mutant cell line revealed aberrantly elevated H3K27me3 and decreased monomethylated H3K27 (H3K27me1) and dimethylated H3K27 (H3K27me2). A677G EZH2 possessed catalytic activity with a substrate specificity that was distinct from those of both WT EZH2 and Y641 mutants. Whereas WT EZH2 displayed a preference for substrates with less methylation [unmethylated H3K27 (H3K27me0):me1:me2 k cat / K m ratio = 9:6:1] and Y641 mutants preferred substrates with greater methylation (H3K27me0:me1:me2 k cat / K m ratio = 1:2:13), the A677G EZH2 demonstrated nearly equal efficiency for all three substrates (H3K27me0:me1:me2 k cat / K m ratio = 1.1:0.6:1). When transiently expressed in cells, A677G EZH2, but not WT EZH2, increased global H3K27me3 and decreased H3K27me2. Structural modeling of WT and mutant EZH2 suggested that the A677G mutation acquires the ability to methylate H3K27me2 through enlargement of the lysine tunnel while preserving activity with H3K27me0/me1 substrates through retention of the Y641 residue that is crucial for orientation of these smaller substrates. This mutation highlights the interplay between Y641 and A677 residues in the substrate specificity of EZH2 and identifies another lymphoma patient population that harbors an activating mutation of EZH2.
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Citations
Cites
High-Resolution Profiling of Histone Methylations in the Human Genome
Barski, A., Cuddapah, S., Cui, K., Roh, T.-Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., & Zhao, K. (2007) · Cell · doi:10.1016/j.cell.2007.05.009 · Cited by 6,845
Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
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Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
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EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.
Bracken, A. P., Pasini, D., Capra, M., Prosperini, E., Colli, E., & Helin, K. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg542 · Cited by 1,196
Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes
Dalgliesh, G. L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., et al. (2010) · Nature · doi:10.1038/nature08672 · Cited by 1,173 · cited 1×
“(4, 20, 21) and overexpression of EZH2 attributable to multiple mechanisms, including decreased miR-101 levels (22, 23), aberrant E2F activity (24), and chromosomal amplification (25).”
BackgroundInactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Ernst, T., Chase, A. J., Score, J., Hidalgo-Curtis, C. E., Bryant, C., Jones, A. V., Waghorn, K., Zoi, K., Ross, F. M., Reiter, A., et al. (2010) · Nature Genetics · doi:10.1038/ng.621 · Cited by 1,139
Structural Biology of Human H3K9 Methyltransferases
Wu, H., Min, J., Lunin, V. V., Antoshenko, T., Dombrovski, L., Zeng, H., Allali-Hassani, A., Campagna-Slater, V., Vedadi, M., Arrowsmith, C. H., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008570 · Cited by 268
Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies
Makishima, H., Jankowska, A. M., Tiu, R. V., Szpurka, H., Sugimoto, Y., Hu, Z., Saunthararajah, Y., Guinta, K., Keddache, M. A., Putnam, P., et al. (2010) · Leukemia · doi:10.1038/leu.2010.167 · Cited by 179
Cited by
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
McCabe, M. T., Ott, H. M., Ganji, G., Korenchuk, S., Thompson, C., Van Aller, G. S., Liu, Y., Graves, A. P., III, A. D. P., Diaz, E., et al. (2012) · Nature · doi:10.1038/nature11606 · Cited by 1,786
Self-citationKim, K. H., & Roberts, C. W. M. (2016) · Nature Medicine · doi:10.1038/nm.4036 · Cited by 1,471
Writing, erasing and reading histone lysine methylations
Hyun, K., Jeon, J., Park, K., & Kim, J. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.11 · Cited by 1,250
Genome Regulation by Polycomb and Trithorax: 70 Years and Counting
Schuettengruber, B., Bourbon, H.-M., Di Croce, L., & Cavalli, G. (2017) · Cell · doi:10.1016/j.cell.2017.08.002 · Cited by 1,094
A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells
Knutson, S. K., Wigle, T. J., Warholic, N. M., Sneeringer, C. J., Allain, C. J., Klaus, C. R., Sacks, J. D., Raimondi, A., Majer, C. R., Song, J., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1084 · Cited by 776
Metadata
- Authors
- McCabe, M. T., Graves, A. P., Ganji, G., Diaz, E., Halsey, W. S., Jiang, Y., Smitheman, K. N., Ott, H. M., Pappalardi, M. B., Allen, K. E., Chen, S. B., Della Pietra, A., Dul, E., Hughes, A. M., Gilbert, S. A., Thrall, S. H., Tummino, P. J., Kruger, R. G., Brandt, M., Schwartz, B., & Creasy, C. L.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2012-02-08
- Volume
- 109
- Issue
- 8
- Pages
- 2989-2994
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1995275377
- Cited by
- 483
- References
- 11
- FWCI
- 16.84
- Type
- journal article
- Language
- en
- Open access
- green
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- McCabe, M. T., Graves, A. P., Ganji, G., Diaz, E., Halsey, W. S., Jiang, Y., Smitheman, K. N., Ott, H. M., Pappalardi, M. B., Allen, K. E., Chen, S. B., Della Pietra, A., Dul, E., Hughes, A. M., Gilbert, S. A., Thrall, S. H., Tummino, P. J., Kruger, R. G., Brandt, M., . . . Creasy, C. L. (2012). Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1116418109
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