Within a eukaryotic cell, both lipid homeostasis and faithful cell cycle progression are meticulously orchestrated. The fission yeast Schizosaccharomyces pombe provides a powerful platform to study the intricate regulatory mechanisms governing these fundamental processes. In S. pombe, the Cbf11 and Mga2 proteins are transcriptional activators of non-sterol lipid metabolism genes, with Cbf11 also known as a cell cycle regulator. Despite sharing a common set of target genes, little was known about their functional relationship. This study reveals that Cbf11 and Mga2 function together in the same regulatory pathway, critical for both lipid metabolism and mitotic fidelity. Deletion of either gene results in a similar array of defects, including slow growth, dysregulated lipid homeostasis, impaired cell cycle progression (cut phenotype), abnormal cell morphology, perturbed transcriptomic and proteomic profiles, and compromised response to the stressors camptothecin and thiabendazole. Remarkably, the double deletion mutant does not exhibit a more severe phenotype compared to the single mutants. In addition, ChIP-nexus analysis reveals that both Cbf11 and Mga2 bind to nearly identical positions within the promoter regions of target genes. Interestingly, Mga2 binding appears to be dependent on the presence of Cbf11 and Cbf11 likely acts as a tether to DNA, while Mga2 is needed to activate the target genes. In addition, the study explores the distribution of Cbf11 and Mga2 homologs across fungi. The presence of both Cbf11 and Mga2 homologs in Basidiomycota contrasts with Ascomycota, which mostly lack Cbf11 but retain Mga2. This suggests an evolutionary rewiring of the regulatory circuitry governing lipid metabolism and mitotic fidelity. In conclusion, this study offers compelling support for Cbf11 and Mga2 functioning jointly to regulate lipid metabolism and mitotic fidelity in fission yeast.

• MeSH
• Lipid Metabolism * genetics   MeSH
• Mitosis * genetics   MeSH
• Gene Expression Regulation, Fungal * MeSH
• Schizosaccharomyces pombe Proteins * genetics   metabolism   MeSH
• Schizosaccharomyces * genetics   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Schizosaccharomyces pombe Proteins * MeSH
• Transcription Factors MeSH

Oxidative stress is associated with cardiovascular and neurodegenerative diseases, diabetes, cancer, psychiatric disorders and aging. In order to counteract, eliminate and/or adapt to the sources of stress, cells possess elaborate stress-response mechanisms, which also operate at the level of regulating transcription. Interestingly, it is becoming apparent that the metabolic state of the cell and certain metabolites can directly control the epigenetic information and gene expression. In the fission yeast Schizosaccharomyces pombe, the conserved Sty1 stress-activated protein kinase cascade is the main pathway responding to most types of stresses, and regulates the transcription of hundreds of genes via the Atf1 transcription factor. Here we report that fission yeast cells defective in fatty acid synthesis (cbf11, mga2 and ACC/cut6 mutants; FAS inhibition) show increased expression of a subset of stress-response genes. This altered gene expression depends on Sty1-Atf1, the Pap1 transcription factor, and the Gcn5 and Mst1 histone acetyltransferases, is associated with increased acetylation of histone H3 at lysine 9 in the corresponding gene promoters, and results in increased cellular resistance to oxidative stress. We propose that changes in lipid metabolism can regulate the chromatin and transcription of specific stress-response genes, which in turn might help cells to maintain redox homeostasis.

• MeSH
• Acetyltransferases genetics   MeSH
• Chromatin * metabolism   MeSH
• Gene Expression MeSH
• Phosphorylation MeSH
• Lipid Metabolism * MeSH
• Mitogen-Activated Protein Kinases metabolism   MeSH
• Oxidative Stress * MeSH
• Gene Expression Regulation, Fungal MeSH
• Schizosaccharomyces pombe Proteins * genetics   MeSH
• Schizosaccharomyces * genetics   MeSH
• Basic-Leucine Zipper Transcription Factors genetics   MeSH
• Transcription Factors genetics   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetyltransferases MeSH
• Cbf11 protein, S pombe MeSH Browser
• Chromatin * MeSH
• Gcn5 protein, S pombe MeSH Browser
• Mitogen-Activated Protein Kinases MeSH
• Pap1 protein, S pombe MeSH Browser
• Schizosaccharomyces pombe Proteins * MeSH
• Basic-Leucine Zipper Transcription Factors MeSH
• Transcription Factors MeSH

For every eukaryotic cell to grow and divide, intricately coordinated action of numerous proteins is required to ensure proper cell-cycle progression. The fission yeast Schizosaccharomyces pombe has been instrumental in elucidating the fundamental principles of cell-cycle control. Mutations in S. pombe 'cut' (cell untimely torn) genes cause failed coordination between cell and nuclear division, resulting in catastrophic mitosis. Deletion of cbf11, a fission yeast CSL transcription factor gene, triggers a 'cut' phenotype, but the precise role of Cbf11 in promoting mitotic fidelity is not known. We report that Cbf11 directly activates the transcription of the acetyl-coenzyme A carboxylase gene cut6, and the biotin uptake/biosynthesis genes vht1 and bio2, with the former 2 implicated in mitotic fidelity. Cbf11 binds to a canonical, metazoan-like CSL response element (GTGGGAA) in the cut6 promoter. Expression of Cbf11 target genes shows apparent oscillations during the cell cycle using temperature-sensitive cdc25-22 and cdc10-M17 block-release experiments, but not with other synchronization methods. The penetrance of catastrophic mitosis in cbf11 and cut6 mutants is nutrient-dependent. We also show that drastic decrease in biotin availability arrests cell proliferation but does not cause mitotic defects. Taken together, our results raise the possibility that CSL proteins play conserved roles in regulating cell-cycle progression, and they could guide experiments into mitotic CSL functions in mammals.

• Keywords
• Schizosaccharomyces pombe, biotin, catastrophic mitosis, cut, periodic gene expression, premature cytokinesis, transcription factor,
• MeSH
• Biotin metabolism   MeSH
• DNA, Fungal metabolism   MeSH
• Epistasis, Genetic MeSH
• Transcription, Genetic MeSH
• Genes, Fungal * MeSH
• Mitosis genetics   MeSH
• Mutation genetics   MeSH
• Promoter Regions, Genetic MeSH
• Gene Expression Regulation, Fungal * MeSH
• Schizosaccharomyces pombe Proteins genetics   metabolism   MeSH
• Schizosaccharomyces cytology   genetics   MeSH
• Protein Binding genetics   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biotin MeSH
• DNA, Fungal MeSH
• Schizosaccharomyces pombe Proteins MeSH

BACKGROUND: Cbf11 and Cbf12, the fission yeast CSL transcription factors, have been implicated in the regulation of cell-cycle progression, but no specific roles have been described and their target genes have been only partially mapped. METHODOLOGY/PRINCIPAL FINDINGS: Using a combination of transcriptome profiling under various conditions and genome-wide analysis of CSL-DNA interactions, we identify genes regulated directly and indirectly by CSL proteins in fission yeast. We show that the expression of stress-response genes and genes that are expressed periodically during the cell cycle is deregulated upon genetic manipulation of cbf11 and/or cbf12. Accordingly, the coordination of mitosis and cytokinesis is perturbed in cells with genetically manipulated CSL protein levels, together with other specific defects in cell-cycle progression. Cbf11 activity is nutrient-dependent and Δcbf11-associated defects are mitigated by inactivation of the protein kinase A (Pka1) and stress-activated MAP kinase (Sty1p38) pathways. Furthermore, Cbf11 directly regulates a set of lipid metabolism genes and Δcbf11 cells feature a stark decrease in the number of storage lipid droplets. CONCLUSIONS/SIGNIFICANCE: Our results provide a framework for a more detailed understanding of the role of CSL proteins in the regulation of cell-cycle progression in fission yeast.

• MeSH
• Cytokinesis MeSH
• Stress, Physiological MeSH
• Mitogen-Activated Protein Kinases genetics   MeSH
• Mitosis MeSH
• Cyclic AMP-Dependent Protein Kinases genetics   MeSH
• Gene Expression Regulation, Fungal MeSH
• Schizosaccharomyces pombe Proteins genetics   metabolism   MeSH
• Schizosaccharomyces genetics   metabolism   MeSH
• Gene Expression Profiling methods   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cbf11 protein, S pombe MeSH Browser
• Cbf12 protein, S pombe MeSH Browser
• Mitogen-Activated Protein Kinases MeSH
• Cyclic AMP-Dependent Protein Kinases MeSH
• Schizosaccharomyces pombe Proteins MeSH
• sty1 protein, S pombe MeSH Browser
• Transcription Factors MeSH