Metabolic control of the G1/S transition - a new model of Start

• Applicant: Professorin Jennifer Christina Ewald, Ph.D.
• Subject Area: Cell Biology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391105827

Metabolic Control of the G1/S transition – A new model for StartGrowth and division are regulated in response to nutrients. If nutrient supply is insufficient, cells do not commit to another round of division. The decision to irreversibly commit to the cell cycle takes place in G1 at the “restriction point” in mammals and “Start” in yeast, our model of choice. While clearly nutrient supply affects Start, it is not clear how nutrient supply affects yeast cells that have already passed Start.By analysing single cells, we found that nutrient-deprivation can delay all phases of the cell cycle. Some starved cells showed a surprising behaviour: The cell cycle inhibitor Whi5, whose nuclear exit allows CDK activation at Start, can re-enter the nucleus. Whi5 nuclear re-entry cannot be explained by the current model of irreversible cell cycle commitment. This reversal of Start happens any time before replication begins, and is caused by dephosphorylation of Whi5, downstream of Snf1 signalling.If Start is not the final point of irreversibility, then what is? Which downstream regulators integrate nutrient signalling for the final decision? And do cells maintain a memory of CDK activation? To solve these questions, we will now combine single cell analysis with protein biochemistry In mammals, the model of a universal restriction point has been challenged, but a consensus model of cell cycle commitment as a multi-step process is still lacking. Our discovery that also in yeast cell cycle commitment is a multi-step process, provides an excellent simpler model to gain a mechanistic understanding of eukaryotic G1/S control.

• DFG Programme: Research Grants