title: The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states.
abstract: Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of EZH2 have been identified in patients with certain subtypes of non-Hodgkin lymphoma (NHL). These mutations were shown to change the substrate specificity of EZH2 for various methylation states of lysine 27 on histone H3 (H3K27). An additional mutation at EZH2 Y641 to cysteine (Y641C) was also found in one patient with NHL and in SKM-1 cells derived from a patient with myelodisplastic syndrome (MDS). The Y641C mutation has been reported to dramatically reduce enzymatic activity. Here, we demonstrate that while the Y641C mutation ablates enzymatic activity against unmethylated and monomethylated H3K27, it is superior to wild-type in catalyzing the formation of trimethylated H3K27 from the dimethylated precursor.
authors.affiliation: Epizyme, Inc., 325 Vassar St., Cambridge, MA 02139, USA. twigle@epizyme.com
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Margaret Porter
authors.initials: MP
authors.lastname: Scott
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D008969:Molecular Sequence Data; D009154:Mutation; D063151:Polycomb Repressive Complex 2; D017422:Sequence Analysis, DNA; D013379:Substrate Specificity / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine; D003545:Cysteine