Implications of alternative routes to APC/C inhibition by the mitotic checkpoint complex.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238922 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7358 (Electronic) Linking ISSN: 1553734X NLM ISO Abbreviation: PLoS Comput Biol Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, [2005]-

Anaphase-Promoting Complex-Cyclosome* ; Chromosome Segregation*; Cdc20 Proteins/*metabolism ; Cell Cycle Proteins/*metabolism ; Mitosis/*genetics ; Schizosaccharomyces/*cytology ; Schizosaccharomyces pombe Proteins/*metabolism; Anaphase ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Nucleus/metabolism ; Models, Theoretical ; Protein Binding ; Signal Transduction ; Spindle Apparatus/metabolism

The mitotic checkpoint (also called spindle assembly checkpoint) is a signaling pathway that ensures faithful chromosome segregation. Mitotic checkpoint proteins inhibit the anaphase-promoting complex (APC/C) and its activator Cdc20 to prevent precocious anaphase. Checkpoint signaling leads to a complex of APC/C, Cdc20, and checkpoint proteins, in which the APC/C is inactive. In principle, this final product of the mitotic checkpoint can be obtained via different pathways, whose relevance still needs to be fully ascertained experimentally. Here, we use mathematical models to compare the implications on checkpoint response of the possible pathways leading to APC/C inhibition. We identify a previously unrecognized funneling effect for Cdc20, which favors Cdc20 incorporation into the inhibitory complex and therefore promotes checkpoint activity. Furthermore, we find that the presence or absence of one specific assembly reaction determines whether the checkpoint remains functional at elevated levels of Cdc20, which can occur in cancer cells. Our results reveal the inhibitory logics behind checkpoint activity, predict checkpoint efficiency in perturbed situations, and could inform molecular strategies to treat malignancies that exhibit Cdc20 overexpression.
Competing Interests: The authors have declared that no competing interests exist.

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R35 GM119723 United States GM NIGMS NIH HHS

0 (Cdc20 Proteins)
0 (Cdc20 protein, S pombe)
0 (Cell Cycle Proteins)
0 (Schizosaccharomyces pombe Proteins)
EC 2.3.2.27 (Anaphase-Promoting Complex-Cyclosome)

Date Created: 20180911 Date Completed: 20190130 Latest Revision: 20190412

20250114

PMC6157902

10.1371/journal.pcbi.1006449

30199529