Article ; Online: Functional tug of war between kinases, phosphatases, and the Gcn5 acetyltransferase in chromatin and cell cycle checkpoint controls.
2023 Volume 13, Issue 4
Abstract: Covalent modifications of chromatin regulate genomic structure and accessibility in diverse biological processes such as transcriptional regulation, cell cycle progression, and DNA damage repair. Many histone modifications have been characterized, yet ... ...
| Abstract | Covalent modifications of chromatin regulate genomic structure and accessibility in diverse biological processes such as transcriptional regulation, cell cycle progression, and DNA damage repair. Many histone modifications have been characterized, yet understanding the interactions between these and their combinatorial effects remains an active area of investigation, including dissecting functional interactions between enzymes mediating these modifications. In budding yeast, the histone acetyltransferase Gcn5 interacts with Rts1, a regulatory subunit of protein phosphatase 2A (PP2A). Implicated in the interaction is the potential for the dynamic phosphorylation of conserved residues on histone H2B and the Cse4 centromere-specific histone H3 variant. To probe these dynamics, we sought to identify kinases which contribute to the phosphorylated state. In a directed screen beginning with in silico analysis of the 127 members of yeast kinome, we have now identified 16 kinases with genetic interactions with GCN5 and specifically found distinct roles for the Hog1 stress-activated protein kinase. Deletion of HOG1 (hog1Δ) rescues gcn5Δ sensitivity to the microtubule poison nocodazole and the lethality of the gcn5Δ rts1Δ double mutant. The Hog1-Gcn5 interaction requires the conserved H2B-T91 residue, which is phosphorylated in vertebrate species. Furthermore, deletion of HOG1 decreases aneuploidy and apoptotic populations in gcn5Δ cells. Together, these results introduce Hog1 as a kinase that functionally opposes Gcn5 and Rts1 in the context of the spindle assembly checkpoint and suggest further kinases may also influence GCN5's functions. |
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| MeSH term(s) | Chromatin/genetics ; Chromatin/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Phosphoric Monoester Hydrolases/genetics ; Chromosomes/metabolism ; Histones/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Histone Acetyltransferases/metabolism ; Cell Cycle Checkpoints ; Chromosomal Proteins, Non-Histone/metabolism ; DNA-Binding Proteins/genetics |
| Chemical Substances | Chromatin ; Saccharomyces cerevisiae Proteins ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; Histones ; Histone Acetyltransferases (EC 2.3.1.48) ; GCN5 protein, S cerevisiae (EC 2.3.1.48) ; CSE4 protein, S cerevisiae ; Chromosomal Proteins, Non-Histone ; DNA-Binding Proteins |
| Language | English |
| Publishing date | 2023-02-10 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2629978-1 |
| ISSN | 2160-1836 ; 2160-1836 |
| ISSN (online) | 2160-1836 |
| ISSN | 2160-1836 |
| DOI | 10.1093/g3journal/jkad021 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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