Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control

TL;DR

This study demonstrates through modeling and simulations that the spindle assembly checkpoint (SAC) is sufficient to fully sequester Cdc20 and inhibit APC/C activity, ensuring proper mitotic control and genome fidelity.

Contribution

The paper presents a dynamic systems biology model showing SAC's sufficiency in Cdc20 sequestration and APC/C inhibition, validated with experimental data.

Findings

SAC fully sequesters Cdc20 to inhibit APC/C

Model aligns with experimental observations

Highlights importance of systems biology in molecular regulation

Abstract

The spindle checkpoint assembly (SAC) ensures genome fidelity by temporarily delaying anaphase onset, until all chromosomes are properly attached to the mitotic spindle. The SAC delays mitotic progression by preventing activation of the ubiquitin ligase anaphase-promoting complex (APC/C) or cyclosome; whose activation by Cdc20 is required for sister-chromatid separation marking the transition into anaphase. The mitotic checkpoint complex (MCC), which contains Cdc20 as a subunit, binds stably to the APC/C. Compelling evidence by Izawa and Pines (Nature 2014; 10.1038/nature13911) indicates that the MCC can inhibit a second Cdc20 that has already bound and activated the APC/C. Whether or not MCC per se is sufficient to fully sequester Cdc20 and inhibit APC/C remains unclear. Here, a dynamic model for SAC regulation in which the MCC binds a second Cdc20 was constructed. This model is compared to the MCC, and the MCC-and-BubR1 (dual inhibition of APC) core model variants and subsequently validated with experimental data from the literature. By using ordinary nonlinear differential equations and spatial simulations, it is shown that the SAC works sufficiently to fully sequester Cdc20 and completely inhibit APC/C activity. This study highlights the principle that a systems biology approach is vital for molecular biology and could also be used for creating hypotheses to design future experiments.