Chromatin Signaling to Kinetochores: Transregulation of Dam1 Methylation by Histone H2B Ubiquitination

Abstract

Summary Histone H3K4 trimethylation by the Set1/MLL family of proteins provides a hallmark for transcriptional activity from yeast to humans. In S. cerevisiae, H3K4 methylation is mediated by the Set1-containing COMPASS complex and is regulated in trans by prior ubiquitination of histone H2BK123. All of the events that regulate H2BK123ub and H3K4me are thought to occur at gene promoters. Here we report that this pathway is indispensable for methylation of the only other known substrate of Set1, K233 in Dam1, at kinetochores. Deletion of RAD6, BRE1, or Paf1 complex members abolishes Dam1 methylation, as does mutation of H2BK123. Our results demonstrate that Set1-mediated methylation is regulated by a general pathway regardless of substrate that is composed of transcriptional regulatory factors functioning independently of transcription. Moreover, our data identify a node of regulatory cross-talk in trans between a histone modification and modification on a non-histone protein, demonstrating that changing chromatin states can signal functional changes in other essential cellular proteins and machineries.

The Set1/COMPASS Histone H3 Methyltransferase Helps Regulate Mitosis With the CDK1 and NIMA Mitotic Kinases in Aspergillus nidulans

“…The findings implicate the Set1 complex in regulating mitotic entry with mitotic CDK1 activation and in regulating progression through mitosis with NIMA. Our results extend the mitotic regulatory systems in which the Set1 complex is involved, beyond its previously defined functions with the budding yeast Aurora kinase at the kinetochore involving Dam1 methylation (Zhang et al 2005;Latham et al 2011).…”

“…The findings implicate the Set1 complex in regulating mitotic entry with mitotic CDK1 activation and in regulating progression through mitosis with NIMA. Our results extend the mitotic regulatory systems in which the Set1 complex is involved, beyond its previously defined functions with the budding yeast Aurora kinase at the kinetochore involving Dam1 methylation (Zhang et al 2005;Latham et al 2011).The synthetic lethality caused by Set1 mutation and impairment of mitotic CDK1 or NIMA kinase activity involves the Set1 substrate histone H3K4The synthetic genetic interaction of the gene encoding the catalytic protein An-set1 in addition to the Set1 complex subunit An-swd1 with the NIMA and CDK1 mitotic kinases indicates that the loss of methyltransferase activity of the Set1 complex is responsible for the genetic interactions. Our analysis confirmed that Swd1 and Set1 were both required for histone H3K4 mono-, di-, and trimethylation in A. nidulans.…”

“…Our analysis confirmed that Swd1 and Set1 were both required for histone H3K4 mono-, di-, and trimethylation in A. nidulans. Although the most well conserved substrate of the Set1 complex is the histone H3K4 site, Set1 is also known to methylate the kinetochore protein Dam1 in S. cerevisiae (Zhang et al 2005;Latham et al 2011) to regulate kinetochore functions. If preventing methylation at H3K4 showed similar genetic interactions with NIMA and CDK1 as the absence of An-set1 or An-swd1, this would support the hypothesis that the absence of Set1 complex-mediated H3K4 methylation causes the genetic interactions.…”

“…Growing evidence indicates that the Set1 complex is involved in a gamut of additional cellular functions, many of which may be independent of its roles in gene expression, including kinetochore maintenance, DNA repair, and replication checkpoints (Faucher and Wellinger 2010;Bergmann et al 2011). Importantly the Set1 complex regulates mitosis in budding yeast with the Aurora mitotic kinase Ipl1 and the type1 phosphatase Glc7 (Zhang et al 2005;Latham et al 2011). This mitotic function involves a second Set1 target substrate, the inner kinetochore protein Dam1.…”

Kinases and chromatin structure

“…[17][18][19][20][21][22][23][24] The laboratories of Steve Jackson and Sharon Dent recently revealed an additional layer of complexity in the role of the chromatin structure. 25,26 Their studies nicely show that changes in the chromatin structure can actually act upstream of signaling pathways and signal to the cell. JNK signaling in mouse embryonic stem cells severely impairs their in vitro differentiation into neurons.…”