H3K27 (histone H3 Lys27) methylation is an important epigenetic modification that regulates gene transcription. In humans, EZH (enhancer of zeste homologue) 1 and EZH2 are the only enzymes capable of catalysing methylation of H3K27. There is great interest in understanding structure–function relationships for EZH2, as genetic alterations in this enzyme are thought to play a causal role in a number of human cancers. EZH2 is challenging to study because it is only active in the context of the multi-subunit PRC2 (polycomb repressive complex 2). vSET is a viral lysine methyltransferase that represents the smallest protein unit capable of catalysing H3K27 methylation. The crystal structure of this minimal catalytic protein has been solved and researchers have suggested that vSET might prove useful as an EZH2 surrogate for the development of active site-directed inhibitors. To test this proposition, we conducted comparative enzymatic analysis of human EZH2 and vSET and report that, although both enzymes share similar preferences for methylation of H3K27, they diverge in terms of their permissiveness for catalysing methylation of alternative histone lysine sites, their relative preferences for utilization of multimeric macromolecular substrates, their active site primary sequences and, most importantly, their sensitivity to inhibition by drug-like small molecules. The cumulative data led us to suggest that EZH2 and vSET have very distinct active site structures, despite the commonality of the reaction catalysed by the two enzymes. Hence, the EZH2 and vSET pair of enzymes represent an example of convergent evolution in which distinct structural solutions have developed to solve a common catalytic need.
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Research Article|
June 28 2013
Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys27 methylation by human polycomb repressive complex 2 and vSET
Brooke M. Swalm;
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
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Kenneth K. Hallenbeck;
Kenneth K. Hallenbeck
1
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
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Christina R. Majer;
Christina R. Majer
2
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
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Lei Jin;
Lei Jin
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
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Margaret Porter Scott;
Margaret Porter Scott
2
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
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Mikel P. Moyer;
Mikel P. Moyer
2
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
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Robert A. Copeland;
Robert A. Copeland
2
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
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Tim J. Wigle
1Epizyme Inc., 400 Technology Square, Cambridge, MA 02139, U.S.A.
3To whom correspondence should be addressed (email twigle@epizyme.com).
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Publisher: Portland Press Ltd
Received:
March 25 2013
Revision Received:
May 06 2013
Accepted:
May 17 2013
Accepted Manuscript online:
May 17 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 453 (2): 241–247.
Article history
Received:
March 25 2013
Revision Received:
May 06 2013
Accepted:
May 17 2013
Accepted Manuscript online:
May 17 2013
Citation
Brooke M. Swalm, Kenneth K. Hallenbeck, Christina R. Majer, Lei Jin, Margaret Porter Scott, Mikel P. Moyer, Robert A. Copeland, Tim J. Wigle; Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys27 methylation by human polycomb repressive complex 2 and vSET. Biochem J 15 July 2013; 453 (2): 241–247. doi: https://doi.org/10.1042/BJ20130439
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