Positive feedback sharpens the anaphase switch

Publisher Website
Google Scholar
Abstract
The cell cycle couples growth and cell division to ensure the consistent size and shape of individual cells. This involves a vast array of genes and proteins, and requires sophisticated mechanisms to keep them acting in step. Two reports in this issue focus on different points in the cell cycle of the budding yeast Saccharomyces cerevisiae, and find that in each case, positive feedback keeps the process on the rails. Skotheim et al. studied the Start checkpoint in the G1 cell cycle phase, where cells irreversibly commit to cell division. Single-cell analysis reveals that Start is a positive feedback-dependent switch that coordinates the simultaneous transcription of a large group of cell cycle genes and the budding of a daughter cell. Holt et al. studied the onset of anaphase in mitosis, at which chromosome pairs separate abruptly and simultaneously. Cohesion between sister chromatids is dissolved by the enzyme separase, which is held in check by securin. A positive feedback loop regulating the ubiquitination and destruction of securin appears to make anaphase a switch-like event. Chromosomes separate abruptly during anaphase of mitosis, but how this switch-like behaviour is achieved is unclear. Cohesion between sister chromatids is dissolved by the protease separase, which is held in check by securin. In this paper, a positive feedback loop regulating the ubiquitination and destruction of securin is proposed to make anaphase more switch-like. At the onset of anaphase, sister-chromatid cohesion is dissolved abruptly and irreversibly, ensuring that all chromosome pairs disjoin almost simultaneously. The regulatory mechanisms that generate this switch-like behaviour are unclear. Anaphase is initiated when a ubiquitin ligase, the anaphase-promoting complex (APC), triggers the destruction of securin, thereby allowing separase, a protease, to disrupt sister-chromatid cohesion1,2,3,4. Here we demonstrate that the cyclin-dependent kinase 1 (Cdk1)-dependent phosphorylation of securin near its destruction-box motif inhibits securin ubiquitination by the APC. The phosphatase Cdc14 reverses securin phosphorylation, thereby increasing the rate of securin ubiquitination. Because separase is known to activate Cdc14 (refs 5 and 6), our results support the existence of a positive feedback loop that increases the abruptness of anaphase. Consistent with this model, we show that mutations that disrupt securin phosphoregulation decrease the synchrony of chromosome segregation. Our results also suggest that coupling securin degradation with changes in Cdk1 and Cdc14 activities helps coordinate the initiation of sister-chromatid separation with changes in spindle dynamics.