Regulation of the Histone Deacetylase Hst3 by Cyclin-dependent Kinases and the Ubiquitin Ligase SCFCdc4

• Published in: The Journal of biological chemistry Vol. 289; no. 19; pp. 13186 - 13196
• Main Authors: Delgoshaie, Neda, Tang, Xiaojing, Kanshin, Evgeny D., Williams, Elizabeth C., Rudner, Adam D., Thibault, Pierre, Tyers, Mike, Verreault, Alain
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.05.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation; CDK (Cyclin-dependent Kinase); Cell Cycle - physiology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chromatin Histone Modification; DNA and Chromosomes; E3 Ubiquitin Ligase; Enzyme Stability - physiology; F-Box Proteins - genetics; F-Box Proteins - metabolism; Genome, Fungal - physiology; Histone Deacetylase; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Histones - genetics; Histones - metabolism; Phosphorylation - physiology; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitination - physiology; CDK (Cyclin-dependent Kinase); Chromatin Histone Modification; Histones; E3 Ubiquitin Ligase; Ubiquitination; Histone Deacetylase
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M113.523530

In Saccharomyces cerevisiae, histone H3 lysine 56 acetylation (H3K56ac) is a modification of new H3 molecules deposited throughout the genome during S-phase. H3K56ac is removed by the sirtuins Hst3 and Hst4 at later stages of the cell cycle. Previous studies indicated that regulated degradation of Hst3 plays an important role in the genome-wide waves of H3K56 acetylation and deacetylation that occur during each cell cycle. However, little is known regarding the mechanism of cell cycle-regulated Hst3 degradation. Here, we demonstrate that Hst3 instability in vivo is dependent upon the ubiquitin ligase SCFCdc4 and that Hst3 is phosphorylated at two Cdk1 sites, threonine 380 and threonine 384. This creates a diphosphorylated degron that is necessary for Hst3 polyubiquitylation by SCFCdc4. Mutation of the Hst3 diphospho-degron does not completely stabilize Hst3 in vivo, but it nonetheless results in a significant fitness defect that is particularly severe in mutant cells treated with the alkylating agent methyl methanesulfonate. Unexpectedly, we show that Hst3 can be degraded between G2 and anaphase, a window of the cell cycle where Hst3 normally mediates genome-wide deacetylation of H3K56. Our results suggest an intricate coordination between Hst3 synthesis, genome-wide H3K56 deacetylation by Hst3, and cell cycle-regulated degradation of Hst3 by cyclin-dependent kinases and SCFCdc4. A genome-wide wave of histone H3 acetylation and deacetylation occurs during the fungal cell cycle. Cyclin-dependent kinases and the ubiquitin ligase SCFCdc4 promote timely degradation of Hst3, a sirtuin involved in genome-wide histone H3 deacetylation. Mutations that interfere with cell cycle-regulated degradation of the Hst3 histone deacetylase reduce cell fitness. Similar regulatory mechanisms may exist in pathogenic fungi.