A Dynamical Model for Activating and Silencing the Mitotic Checkpoint

Richard Henze,Peter Dittrich,Bashar Ibrahim

doi:10.1038/s41598-017-04218-2

Richard Henze, Peter Dittrich + Show 1 more

Open Access

https://doi.org/10.1038/s41598-017-04218-2

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Abstract

The spindle assembly checkpoint (SAC) is an evolutionarily conserved mechanism, exclusively sensitive to the states of kinetochores attached to microtubules. During metaphase, the anaphase-promoting complex/cyclosome (APC/C) is inhibited by the SAC but it rapidly switches to its active form following proper attachment of the final spindle. It had been thought that APC/C activity is an all-or-nothing response, but recent findings have demonstrated that it switches steadily. In this study, we develop a detailed mathematical model that considers all 92 human kinetochores and all major proteins involved in SAC activation and silencing. We perform deterministic and spatially-stochastic simulations and find that certain spatial properties do not play significant roles. Furthermore, we show that our model is consistent with in-vitro mutation experiments of crucial proteins as well as the recently-suggested rheostat switch behavior, measured by Securin or CyclinB concentration. Considering an autocatalytic feedback loop leads to an all-or-nothing toggle switch in the underlying core components, while the output signal of the SAC still behaves like a rheostat switch. The results of this study support the hypothesis that the SAC signal varies with increasing number of attached kinetochores, even though it might still contain toggle switches in some of its components.

Highlights

Correct DNA segregation is a fundamental process during mitosis that relies on amphitelic attachment between chromosomes, principally through kinetochores and spindle microtubules
Collin et al have recently shown that this is not the case[10]. They postulate that the anaphase-promoting complex/cyclosome (APC/C) inhibitor mitotic checkpoint complex (MCC) is active at different levels, depending on the number of unattached kinetochores, resulting in an active APC/C during metaphase
It achieves this through a robust switch in APC/C activity, but the details of how this switch works have remained elusive

Summary

Introduction

Correct DNA segregation is a fundamental process during mitosis that relies on amphitelic attachment between chromosomes, principally through kinetochores and spindle microtubules. Dynein on the attached kinetochores releases p31comet 6, 7, which lowers the concentration threshold necessary for UbcH10 to become active[5] In this way, p31comet and UbcH10 collaborate to silence the SAC. Ubiquitinated CyclinB releases Cdk[1], initiating mitotic exit (cf Fig. 1) This switch from inactive to active APC/C was believed to be an all-or-nothing response, meaning that once all kinetochores are attached APC/C starts degrading Securin and CyclinB. Collin et al have recently shown that this is not the case[10] They postulate that the APC/C inhibitor MCC is active at different levels, depending on the number of unattached kinetochores, resulting in an active APC/C during metaphase. Models by Ibrahim and colleagues provide detailed descriptions of human SAC activation but lack a realistic explanation for the switch[16,17,18]. They use a manually-activated switch that enables or disables certain reactions according to one of two phases (active and silenced SAC)

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Conclusion