Autonomous Metabolic Oscillations Robustly Gate the Early and Late Cell Cycle

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. [Display omitted] •Metabolic cycles are an intrinsic, growth-condition-independent behavior of single cells•The metabolic oscillations are not the result of the cell cycle and thus are autonomous•The metabolic oscillator and the cyclin/CDK machinery form a system of coupled oscillators•Both the early and late cell cycle operate in coordination with the metabolic oscillator Papagiannakis et al. performed metabolite and cell-cycle measurements in single cells to show that the cell cycle is a higher-order function, which emerges from the collective synchrony between an autonomous metabolic oscillator, a biomass formation oscillator (early cell cycle), and a biomass segregation oscillator (late cell cycle).