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

Andria Schibler, Evangelia Koutelou, Junya Tomida, Marenda Wilson-Pham, Li Wang, Yue Lu, Alexa Parra Cabrera, Renee J. Chosed, Wenqian Li, Bing Li, Xiaobing Shi, Richard D. Wood, Sharon Y R Dent

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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. Wefound 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.

Original languageEnglish (US)
Pages (from-to)1187-1197
Number of pages11
JournalGenes and Development
Issue number10
StatePublished - May 15 2016


  • Chromatin
  • H3K4
  • HORMA domain
  • Lysine methylation
  • Set1
  • Spindle assembly checkpoint

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology


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