  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.
