Final Report Summary - SYNTHECYCLE (Architecture and logic of the eukaryotic cell cycle)
A first aim of our studies focused on how the temporal activity profile of the cyclin-dependent protein kinase (CDK), the major regulator of cell proliferation in eukaryotes, shapes cell proliferation. One question that we addressed is the mechanism by which cells deal with the variability that is inherent to any biological process, in our case cell division. We demonstrated that the CDK pattern defines the sensitivity of cell to noise in the CDK signal. This novel model provides a rationale for the way cells regulate CDK activity to promote robustness in cell proliferation. In a second part, we have investigated the fundamental reasons for the complexity in cell cycle control that is observed in all eukaryotes, building on the initial observation that our simplified cells are indistinguishable from normal cells for their growth and division. Strikingly, we found a link between the regulation of cell proliferation and cellular aging. Indeed, we revealed that the removal of parts of the control system, which seemed to have no particular effects on cellular physiology, changes the way these cells age, and we investigated the mechanisms underlying these changes. This work unravelled a new and unexpected function for the organisation of the intricate network that regulates the cell cycle. Finally, we asked whether and how cells might overcome challenges to their proliferation in the context of a simplified cell cycle network. We performed experimental evolution assays using cells operating with an artificial and impaired cell cycle, maintaining them in various conditions over hundreds of generations. This led to the emergence of evolved clones that have overcome their cell cycle defect. Our results identified novel and unanticipated regulators of the cell cycle and revealed alternative pathways that cells can employ to adapt and evolve..
Our project has therefore addressed a broad range of phenomena and mechanisms closely associated with the way the cell cycle is controlled in eukaryotes. Our unique approach, based on the engineering of minimal and controllable cell cycle networks in living yeast cells, has allowed us to explore areas of cell cycle regulation that could not be studied with conventional strategies and to reveal unanticipated aspects of the regulation and evolution of cell proliferation.