title: Reaction coupling between wild-type and disease-associated mutant EZH2.
abstract: EZH2 and EZH1 are protein methyltransferases (PMTs) responsible for histone H3, lysine 27 (H3K27) methylation. Trimethylation of H3K27 (H3K27me3) is a hallmark of many cancers, including non-Hodgkin lymphoma (NHL). Heterozygous EZH2 point mutations at Tyr641, Ala677, and Ala687 have been observed in NHL. The Tyr641 mutations enhance activity on H3K27me2 but have weak or no activity on unmethylated H3K27, whereas the Ala677 and Ala687 mutations use substrates of all methylation states effectively. It has been proposed that enzymatic coupling of the wild-type and mutant enzymes leads to the oncogenic H3K27me3 mark in mutant-bearing NHL. We show that coupling with the wild-type enzyme is needed to achieve H3K27me3 for several mutants, but that others are capable of achieving H3K27me3 on their own. All forms of PRC2 (wild-type and mutants) display kinetic signatures that are consistent with a distributive mechanism of catalysis.
authors.affiliation: Epizyme, Inc. 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Swalm
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Warholic
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kuntz
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.forename: Mikel P
authors.initials: MP
authors.lastname: Moyer
authors.forename: Margaret Porter
authors.initials: MP
authors.lastname: Scott
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Wigle
mesh_terms: D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry* / Q000235:genetics
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2