title: Autonomous Metabolic Oscillations Robustly Gate the Early and Late Cell Cycle.
abstract: Eukaryotic cell division is known to be controlled by the cyclin/cyclin dependent kinase (CDK) machinery. However, eukaryotes have evolved prior to CDKs, and cells can divide in the absence of major cyclin/CDK components. We hypothesized that an autonomous metabolic oscillator provides dynamic triggers for cell-cycle initiation and progression. Using microfluidics, cell-cycle reporters, and single-cell metabolite measurements, we found that metabolism of budding yeast is a CDK-independent oscillator that oscillates across different growth conditions, both in synchrony with and also in the absence of the cell cycle. Using environmental perturbations and dynamic single-protein depletion experiments, we found that the metabolic oscillator and the cell cycle form a system of coupled oscillators, with the metabolic oscillator separately gating and maintaining synchrony with the early and late cell cycle. Establishing metabolism as a dynamic component within the cell-cycle network opens new avenues for cell-cycle research and therapeutic interventions for proliferative disorders.
authors.affiliation: Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Papagiannakis
authors.affiliation: Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands.
authors.forename: Bastian
authors.initials: B
authors.lastname: Niebel
authors.affiliation: Probability and Statistics, Johann Bernoulli Institute of Mathematics and Computer Science, University of Groningen, Nijenborgh 9, 9747 AG Groningen, the Netherlands.
authors.forename: Ernst C
authors.initials: EC
authors.lastname: Wit
authors.affiliation: Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands. Electronic address: m.heinemann@rug.nl.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinemann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D005838:Genotype; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008954:Models, Biological; D009154:Mutation; D009249:NADP / Q000378:metabolism; D009991:Oscillometry; D010507:Periodicity; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D009249:NADP; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases
keywords: FRET sensor; NAD(P)H; Saccharomyces cerevisiae; cell cycle; coupled oscillators; cyclin/CDK machinery; metabolic oscillations; microfluidics; single cell; yeast metabolic cycle