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Genes Dev. 2016 May 15;30(10):1187-97. doi: 10.1101/gad.278887.116. Epub 2016 May 19.

Histone H3K4 methylation regulates deactivation of the spindle assembly checkpoint through direct binding of Mad2.

Author information

1
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;
2
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;
3
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;
4
The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
5
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;
6
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
7
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
8
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;

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.

KEYWORDS:

H3K4; HORMA domain; Set1; chromatin; lysine methylation; spindle assembly checkpoint

PMID:
27198228
PMCID:
PMC4888839
DOI:
10.1101/gad.278887.116
[Indexed for MEDLINE]
Free PMC Article

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