A CDK-independent metabolic oscillator orchestrates the budding yeast cell cycle

Eukaryotic cell division is known to be controlled by the cyclin/ 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 singlecell 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 coordinating both the early and late cell cycle. Establishing metabolism as a dynamic cell cycle regulator opens new avenues for cell cycle research and therapeutic interventions for proliferative disorders.