S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3

Journal Article · Mon May 16 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1605523113· OSTI ID:1258671

Jayaram, Hariharan ^[1]; Hoelper, Dominik ^[2]; Jain, Siddhant U. ^[2]; Cantone, Nico ^[1]; Lundgren, Stefan M. ^[2]; Poy, Florence ^[1]; Allis, C. David ^[3]; Cummings, Richard ^[1]; Bellon, Steven ^[1]; Lewis, Peter W. ^[2]

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1. Constellation Pharmaceuticals, Cambridge, MA (United States)
2. Univ. of Wisconsin, Madison, WI (United States)
3. Rockefeller Univ., New York, NY (United States)

Lysine to methionine (K-to-M) mutations in genes encoding histone H3 are thought to drive a subset of pediatric brain and bone cancers. These high-frequency K-to-M mutations occur at sites of methylation on histone H3, and tumors containing the mutant histones exhibit a global loss of specific histone methylation marks. Previous studies showed that K-to-M mutant histones, also known as oncohistones, are potent orthosteric inhibitors of specific Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain methyltransferases. However, the biochemical and biophysical details of the interaction between K-to-M mutant histones and the respective SET domain methyltransferases are currently unknown. Here, we use the histone H3K9-directed methyltransferase G9a as a model to explore the mechanism of inhibition by K-to-M oncohistones. X-ray cocrystal structures revealed that the K9M residue of histone H3 occupies the active site cavity of G9a, and kinetic analysis indicates competitive inhibition of G9a by histone H3K9M. Additionally, we find that the cofactorS-adenosyl methionine (SAM) is necessary for stable interaction between G9a and H3K9M histone. Consistent with the formation of a ternary complex, we find that the inhibitory peptide is uncompetitive with regard to SAM. Furthermore, these data and others indicate that K-to-M oncohistones promote global loss of specific lysine methylation through sequestration and inhibition of SAM-bound SET domain methyltransferases.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States)
• Sponsoring Organization: Starr Cancer Consortium; National Institutes of Health (NIH)
• Grant/Contract Number: SCC I6-A614; P01CA196539
• OSTI ID: 1258671
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 22; ISSN 0027-8424
• Publisher: National Academy of Sciences
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
oncohistone
G9a
EHMT2
H3K9me3
K to M