title: Dot1 histone methyltransferases share a distributive mechanism but have highly diverged catalytic properties.
abstract: The conserved histone methyltransferase Dot1 establishes an H3K79 methylation pattern consisting of mono-, di- and trimethylation states on histone H3 via a distributive mechanism. This mechanism has been shown to be important for the regulation of the different H3K79 methylation states in yeast. Dot1 enzymes in yeast, Trypanosoma brucei (TbDot1A and TbDot1B, which methylate H3K76) and human (hDot1L) generate very divergent methylation patterns. To understand how these species-specific methylation patterns are generated, the methylation output of the Dot1 enzymes was compared by expressing them in yeast at various expression levels. Computational simulations based on these data showed that the Dot1 enzymes have highly distinct catalytic properties, but share a distributive mechanism. The mechanism of methylation and the distinct rate constants have implications for the regulation of H3K79/K76 methylation. A mathematical model of H3K76 methylation during the trypanosome cell cycle suggests that temporally-regulated consecutive action of TbDot1A and TbDot1B is required for the observed regulation of H3K76 methylation states.
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Iris J E
authors.initials: IJ
authors.lastname: Stulemeijer
authors.affiliation: Department of Biology, University of Antwerp, Antwerp, 2020, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: De Vos
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: van Harten
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Onkar K
authors.initials: OK
authors.lastname: Joshi
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Olga
authors.initials: O
authors.lastname: Blomberg
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Tibor
authors.initials: T
authors.lastname: van Welsem
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Marit
authors.initials: M
authors.lastname: Terweij
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Vlaming
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics Group, The Netherlands Proteomics Centre, Utrecht University, Utrecht, 3584 CH, The Netherlands.
authors.forename: Erik L
authors.initials: EL
authors.lastname: de Graaf
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics Group, The Netherlands Proteomics Centre, Utrecht University, Utrecht, 3584 CH, The Netherlands.
authors.forename: A F Maarten
authors.initials: AF
authors.lastname: Altelaar
authors.affiliation: Department of Pediatrics, Systems Biology Centre for Energy Metabolism and Ageing, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bakker
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Fred
authors.initials: F
authors.lastname: van Leeuwen
mesh_terms: D002384:Catalysis; D002453:Cell Cycle / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014346:Trypanosoma brucei brucei / Q000201:enzymology* / Q000235:genetics
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D015800:Protozoan Proteins; D029701:Saccharomyces cerevisiae Proteins; C416235:Dot1 protein, S cerevisiae; D011495:Histone-Lysine N-Methyltransferase