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Abstract: The first elaborate metabolic model of Saccharomyces cerevisiae sphingolipid metabolism was reconstructed in silico. The model considers five different states of sphingolipid hydroxylation, rendering it unique among other models. It is aimed to clarify the significance of hydroxylation on sphingolipids and hence to interpret the preferences of the cell between different metabolic pathway branches under different stress conditions. The newly constructed model was validated by single, double and triple gene deletions with experimentally verified phenotypes. Calcium sensitivity and deletion mutations that may suppress calcium sensitivity were examined by CSG1 and CSG2 related deletions. The model enabled the analysis of complex sphingolipid content of the plasma membrane coupled with diacylglycerol and phosphatidic acid biosynthesis and ATP consumption in in silico cell. The flux data belonging to these critically important key metabolites are integrated with the fact of phytoceramide induced cell death to propose novel potential drug targets for cancer therapeutics. In conclusion, we propose that IPT1, GDA1, CSG and AUR1 gene deletions may be novel candidates of drug targets for cancer therapy according to the results of flux balance and variability analyses coupled with robustness analysis. [Copyright &y& Elsevier]

Drugs that act on ribosome biogenesis and cell proliferation play important roles in treatment of human diseases. Moreover, measurement of drug effects at a single-cell level would create vast opportunities for pharmaceutical innovation. We present in this study an original proof-of-concept study of single-cell measurement of drug effects with a focus on inhibition of ribosome biogenesis and cell proliferation, and using yeast (Saccharomyces cerevisiae) as a model eukaryotic organism. We employed a droplet-based microfluidic technology and nucleolar protein-tagged strain of the yeast for real-time monitoring of the cells. We report a comprehensive account of the ways in which interrelated pathways are impacted by drug treatment in a single-cell level. Self-organizing maps, transcription factor, and Gene Ontology enrichment analyses were utilized to these ends. This article makes a contribution to advance single-cell measurement of drug effects. We anticipate the microfluidic technology platform presented herein is well poised for future applications in personalized/precision medicine research as well as in industrial settings for drug discovery and clinical development. In addition, the study offers new insights on ribosome biogenesis and cell proliferation that should prove useful in cancer research and other complex human diseases impacted by these key cellular processes. [ABSTRACT FROM AUTHOR]

Genome instability has long been implicated as a salient causal factor in aging and age-related diseases such as cancer and neurodegeneration. However, the molecular mechanisms associated with genome instability remain unclear. Recent studies suggest growth signaling in the organism Saccharomyces cerevisiae and in higher eukaryotes might affect oxidative stress and aging/age-related diseases by activating DNA replication stress that causes DNA damage. In this broader integrative biology and clinical context, MDM two binding protein (MTBP) is a binding protein that has a role in activation of the tumor suppressor protein p53. Clinical studies suggest that the increase in expression of MTBP leads to reduction in survival of breast cancer patients. The functional homolog of MTBP in yeast, Sld7, is a hitherto uncharacterized protein that decreases the affinity of Sld3 (Treslin/Ticrr in humans) toward Cdc45 in the cell cycle process of S. cerevisiae. To investigate the putative function of Sld7 in chronological aging and replicative life span, we applied a network biology approach, integrating interactome and transcriptome data of budding yeast. The cell cycle and chronological aging networks of proteins in budding yeast were reconstructed. Furthermore, through meta-analysis of cell cycle and chronological aging-associated transcriptome datasets, we constructed coexpression networks and identified coexpressed gene clusters. In this study, we propose a dual role for Sld7: it participates in macromolecular complex binding in the cell cycle and has oxidoreductase activity in chronological aging in budding yeast. These potential roles of Sld7 in yeast can offer new insights on the role of MTBP in humans and consequently might lead to novel strategies for treatment of cancers and aging-related diseases. [ABSTRACT FROM AUTHOR]