Abstract
In Saccharomyces cerevisiae, the conserved phosphatase Cdc14 is required for the exit from mitosis. It is anchored on nucleolar chromatin by the Cfi1/Net1 protein until early anaphase, at which time it is released into the nucleoplasm. Two poorly understood, redundant pathways promote Cdc14 release, the FEAR (Cdc fourteen early release) network and the MEN (mitotic exit network). Through the analysis of genetic interactions, we report here a novel requirement for the ubiquitination of histone H2B by the Bre1 ubiquitin ligase in the cell cycle–dependent release of Cdc14 from nucleolar chromatin when the MEN is inactivated. This function for H2B ubiquitination is mediated by its activation of histone H3 methylation on lysines 4 and 79 (meH3K4 and meH3K79) but, surprisingly, is not dependent on the histone deacetylase (HDAC) Sir2, which associates with Cdc14 on nucleolar chromatin as part of the RENT complex. We also observed a defect in Cdc14 release in cells lacking H3 lysine 36 methylation (meH3K36) and in cells lacking an HDAC recruited by this modification. These histone modifications represent previously unappreciated factors required for the accessibility to and/or action on nucleolar chromatin of FEAR network components. The nonredundant role for these modifications in this context contrasts with the notion of a highly combinatorial code by which histone marks act to control biological processes.
Highlights
To ensure the timely and correct inheritance of sister chromatids followed by cytokinesis, eukaryotic cells have evolved sophisticated regulatory networks
In the S. cerevisiae cell cycle, the exit from the mitotic state is triggered by the release of the phosphatase Cdc14 during the anaphase stage of mitosis from nucleolar chromatin, where it is sequestered and kept inactive
We have discovered that multiple evolutionarily conserved histone modifications are required for the early anaphase release of Cdc14
Summary
To ensure the timely and correct inheritance of sister chromatids followed by cytokinesis, eukaryotic cells have evolved sophisticated regulatory networks. Part of the regulatory complexity involves the requirement that a variety of soluble proteins communicate with tightly chromatin-bound factors on chromosomes. An example of such a mechanism in the budding yeast S. cerevisiae is the control of Cdc, a conserved and essential protein phosphatase. Cdc is kept away from its soluble substrates by being tightly associated with nucleolar chromatin through its inhibitor, the nucleolar protein Cfi1/Net. This interaction is dissolved via the phosphorylation of Cfi/Net, which is necessary for the release of Cdc from the nucleolus [1,2,3]. Liberated Cdc dephosphorylates mitotic Clb cyclin dependent kinases (Clb-CDKs) and their substrates to promote exit from mitosis [3,4,5,6]
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