title: Histone H3K4 methylation regulates deactivation of the spindle assembly checkpoint through direct binding of Mad2.
abstract: Histone H3 methylation on Lys4 (H3K4me) is associated with active gene transcription in all eukaryotes. In Saccharomyces cerevisiae, Set1 is the sole lysine methyltransferase required for mono-, di-, and trimethylation of this site. Although H3K4me3 is linked to gene expression, whether H3K4 methylation regulates other cellular processes, such as mitosis, is less clear. Here we show that both Set1 and H3K4 mutants display a benomyl resistance phenotype that requires components of the spindle assembly checkpoint (SAC), including Bub3 and Mad2. These proteins inhibit Cdc20, an activator of the anaphase-promoting complex/cyclosome (APC/C). Mutations in Cdc20 that block Mad2 interactions suppress the benomyl resistance of both set1 and H3K4 mutant cells. Furthermore, the HORMA domain in Mad2 directly binds H3, identifying a new histone H3 "reader" motif. Mad2 undergoes a conformational change important for execution of the SAC. We found that the closed (active) conformation of both yeast and human Mad2 is capable of binding methylated H3K4, but, in contrast, the open (inactive) Mad2 conformation limits interaction with methylated H3. Collectively, our data indicate that interactions between Mad2 and H3K4 regulate resolution of the SAC by limiting closed Mad2 availability for Cdc20 inhibition.
authors.affiliation: Program in Genes and Development, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; The Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, Texas 77030, USA; Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Andria
authors.initials: A
authors.lastname: Schibler
authors.affiliation: Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Evangelia
authors.initials: E
authors.lastname: Koutelou
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Center for Environmental and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Junya
authors.initials: J
authors.lastname: Tomida
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Marenda
authors.initials: M
authors.lastname: Wilson-Pham
authors.affiliation: The Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, Texas 77030, USA; Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Alexa Parra
authors.initials: AP
authors.lastname: Cabrera
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Chosed
authors.affiliation: The Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, Texas 77030, USA; Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
authors.forename: Wenqian
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Program in Genes and Development, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; The Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, Texas 77030, USA; Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
authors.affiliation: The Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Center for Environmental and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wood
authors.affiliation: The Graduate School of Biomedical Sciences (GSBS) at Houston, Houston, Texas 77030, USA; Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Program in Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
authors.forename: Sharon Y R
authors.initials: SY
authors.lastname: Dent
mesh_terms: D001542:Benomyl / Q000494:pharmacology; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D064246:Mad2 Proteins / Q000378:metabolism*; D008745:Methylation; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000235:genetics / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D064199:Cdc20 Proteins; D006657:Histones; D064246:Mad2 Proteins; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D050257:Tubulin Modulators; D011495:Histone-Lysine N-Methyltransferase; C411250:SET1 protein, S cerevisiae; D001542:Benomyl
keywords: H3K4; HORMA domain; Set1; chromatin; lysine methylation; spindle assembly checkpoint