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

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 cyclosom...

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Autor principal: Ibrahim, Bashar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430708/
https://www.ncbi.nlm.nih.gov/pubmed/25977749
http://dx.doi.org/10.1016/j.csbj.2015.03.006
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author Ibrahim, Bashar
author_facet Ibrahim, Bashar
author_sort Ibrahim, Bashar
collection PubMed
description 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.
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spelling pubmed-44307082015-05-14 Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control Ibrahim, Bashar Comput Struct Biotechnol J Article 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. Research Network of Computational and Structural Biotechnology 2015-04-09 /pmc/articles/PMC4430708/ /pubmed/25977749 http://dx.doi.org/10.1016/j.csbj.2015.03.006 Text en © 2015 Ibrahim. Published by Elsevier B.V. on behalf of the Research Network of Computational and Structural Biotechnology. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Ibrahim, Bashar
Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control
title Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control
title_full Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control
title_fullStr Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control
title_full_unstemmed Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control
title_short Spindle assembly checkpoint is sufficient for complete Cdc20 sequestering in mitotic control
title_sort spindle assembly checkpoint is sufficient for complete cdc20 sequestering in mitotic control
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430708/
https://www.ncbi.nlm.nih.gov/pubmed/25977749
http://dx.doi.org/10.1016/j.csbj.2015.03.006
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