How a dynamic metabolism could control the eukaryotic cell cycle

The eukaryotic cell division is thought to be controlled by periodic activity of the cyclin dependent kinase (CDK) machinery. However, the fact that CDKs came late in the evolution of eukaryotes, and the fact that oscillations in global transcription and the anaphase promoting complex activity were also found in during cell cycle arrest, suggest that cell cycle regulators other than the cyclin/CDK machinery could exist as well. We hypothesized that an autonomous metabolic oscillator could represent such global cell cycle regulator. Using microfluidics technology, in combination with single-cell metabolite and cell cycle reporters, we found that yeast metabolism is a CDK-independent oscillator, which orbits across nutrients and at different metabolic modes, in synchrony with the cell cycle, but also in non-dividing cells. With environmental perturbations and conditional protein depletion experiments, we found that the metabolic oscillator and the cyclin/CDK machinery form a system of coupled oscillators, where the metabolism gates the early and the late cell cycle. Most recently, we have found that the metabolic oscillations emerge from a temporal segregation in the biosynthetic processes. Overall, this work suggests that cell cycle control emerges as a higher order function from coupled and mutually entrained oscillators, including a metabolic/biosynthetic oscillator. Given the evolutionary conservation of metabolic pathways across life kingdoms, such oscillator may constitute an ancestral regulator of cell division.