title: Coordination of Cell Cycle Progression and Mitotic Spindle Assembly Involves Histone H3 Lysine 4 Methylation by Set1/COMPASS.
abstract: Methylation of histone H3 lysine 4 (H3K4) by Set1 complex/COMPASS is a hallmark of eukaryotic chromatin, but it remains poorly understood how this post-translational modification contributes to the regulation of biological processes like the cell cycle. Here, we report a H3K4 methylation-dependent pathway in Saccharomyces cerevisiae that governs toxicity toward benomyl, a microtubule destabilizing drug. Benomyl-sensitive growth of wild-type cells required mono- and dimethylation of H3K4 and Pho23, a PHD-containing subunit of the Rpd3L complex. Δset1 and Δpho23 deletions suppressed defects associated with ipl1-2 aurora kinase mutant, an integral component of the spindle assembly checkpoint during mitosis. Benomyl resistance of Δset1 strains was accompanied by deregulation of all four tubulin genes and the phenotype was suppressed by tub2-423 and Δtub3 mutations, establishing a genetic link between H3K4 methylation and microtubule function. Most interestingly, sine wave fitting and clustering of transcript abundance time series in synchronized cells revealed a requirement for Set1 for proper cell-cycle-dependent gene expression and Δset1 cells displayed delayed entry into S phase. Disruption of G1/S regulation in Δmbp1 and Δswi4 transcription factor mutants duplicated both benomyl resistance and suppression of ipl1-2 as was observed with Δset1 Taken together our results support a role for H3K4 methylation in the coordination of cell-cycle progression and proper assembly of the mitotic spindle during mitosis.
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Traude H
authors.identifier: 0000-0002-8942-9502
authors.initials: TH
authors.lastname: Beilharz
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.|Monash Bioinformatics Platform, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Harrison
authors.affiliation: Marseille Cancer Research Center, U1068 Inserm, UMR7258 CNRS, Aix Marseille University, Institut Paoli-Calmettes, F-13009 Marseille, France. Equipe Labellisée Ligue.
authors.forename: Douglas Maya
authors.initials: DM
authors.lastname: Miles
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Michael Ming
authors.initials: MM
authors.lastname: See
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Uyen Minh Merry
authors.initials: UM
authors.lastname: Le
authors.affiliation: Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Ming
authors.initials: M
authors.lastname: Kalanon
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Melissa Jane
authors.initials: MJ
authors.lastname: Curtis
authors.affiliation: Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Qambar
authors.initials: Q
authors.lastname: Hasan
authors.affiliation: Institute of Human Genetics, UPR 1142, CNRS, 34396 Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Saksouk
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht-Princess Máxima Center for Pediatric Oncology, 3584 Utrecht, The Netherlands.
authors.forename: Thanasis
authors.initials: T
authors.lastname: Margaritis
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht-Princess Máxima Center for Pediatric Oncology, 3584 Utrecht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Holstege
authors.affiliation: Marseille Cancer Research Center, U1068 Inserm, UMR7258 CNRS, Aix Marseille University, Institut Paoli-Calmettes, F-13009 Marseille, France. Equipe Labellisée Ligue Bernhard.Dichtl@deakin.edu.au vincent.geli@inserm.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Geli
authors.affiliation: Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia Bernhard.Dichtl@deakin.edu.au vincent.geli@inserm.fr.
authors.forename: Bernhard
authors.identifier: 0000-0001-5514-4982
authors.initials: B
authors.lastname: Dichtl
mesh_terms: D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D008745:Methylation; D008938:Mitosis / Q000502:physiology; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C411250:SET1 protein, S cerevisiae; D008239:Lysine
keywords: aurora kinase; benomyl; cell cycle; gene expression; histone methylation