TY - JOUR
T1 - Histone H3K4 methylation regulates deactivation of the spindle assembly checkpoint through direct binding of Mad2
AU - Schibler, Andria
AU - Koutelou, Evangelia
AU - Tomida, Junya
AU - Wilson-Pham, Marenda
AU - Wang, Li
AU - Lu, Yue
AU - Cabrera, Alexa Parra
AU - Chosed, Renee J.
AU - Li, Wenqian
AU - Li, Bing
AU - Shi, Xiaobing
AU - Wood, Richard D.
AU - Dent, Sharon Y R
N1 - Publisher Copyright:
© 2016 Schibler et al.
PY - 2016/5/15
Y1 - 2016/5/15
N2 - 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.
AB - 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.
KW - Chromatin
KW - H3K4
KW - HORMA domain
KW - Lysine methylation
KW - Set1
KW - Spindle assembly checkpoint
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U2 - 10.1101/gad.278887.116
DO - 10.1101/gad.278887.116
M3 - Article
C2 - 27198228
AN - SCOPUS:84969769925
SN - 0890-9369
VL - 30
SP - 1187
EP - 1197
JO - Genes and Development
JF - Genes and Development
IS - 10
ER -