Cell Size Control via an Unstable Accumulating Activator and the Phenomenon of Excess Mitotic Delay

Unstable Accumulating Activator models for cellular size control propose an activator that accumulates in a size-dependent manner and triggers cell cycle progression once it has reached a certain threshold. Having a short half life makes such an activator responsive to changes in cell size and makes specific predictions for how cells respond to perturbation. In particular, it explains the curious phenomenon of excess mitotic delay. Excess mitotic delay, first observed in Tetrahymena in the '50s, is a phenomenon in which a pulse of protein synthesis inhibition causes a delay in mitotic entry that is longer than the pulse and that gets longer the later in the cell cycle the pulse is delivered. The interpretation of this phenomenon championed by Zeuthen and Mitchison in the '60s and '70s is that an unstable activator of mitosis is degraded during the pulse and has to be resynthesized to a threshold level to trigger mitosis; small cells have more time to resynthesize the activator before mitosis and so suffer less excess delay, whereas, large cells have less time thus suffer greater excess delay. Fifty years later, with our detailed understanding of cell cycle biochemistry, we can identify and test candidate Unstable Accumulating Activators. Here I review the field and further develop this concept.