A Dynamical Model for Activating and Silencing the Mitotic Checkpoint

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...

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Autores principales:	Richard Henze, Peter Dittrich, Bashar Ibrahim
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1e398d11714a4dff9be9da11317f6f28
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spelling	oai:doaj.org-article:1e398d11714a4dff9be9da11317f6f282021-12-02T16:06:13ZA Dynamical Model for Activating and Silencing the Mitotic Checkpoint10.1038/s41598-017-04218-22045-2322https://doaj.org/article/1e398d11714a4dff9be9da11317f6f282017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04218-2https://doaj.org/toc/2045-2322Abstract 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.Richard HenzePeter DittrichBashar IbrahimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Richard Henze Peter Dittrich Bashar Ibrahim A Dynamical Model for Activating and Silencing the Mitotic Checkpoint
description	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.
format	article
author	Richard Henze Peter Dittrich Bashar Ibrahim
author_facet	Richard Henze Peter Dittrich Bashar Ibrahim
author_sort	Richard Henze
title	A Dynamical Model for Activating and Silencing the Mitotic Checkpoint
title_short	A Dynamical Model for Activating and Silencing the Mitotic Checkpoint
title_full	A Dynamical Model for Activating and Silencing the Mitotic Checkpoint
title_fullStr	A Dynamical Model for Activating and Silencing the Mitotic Checkpoint
title_full_unstemmed	A Dynamical Model for Activating and Silencing the Mitotic Checkpoint
title_sort	dynamical model for activating and silencing the mitotic checkpoint
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1e398d11714a4dff9be9da11317f6f28
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A Dynamical Model for Activating and Silencing the Mitotic Checkpoint

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