Drugs that impair microtubule dynamics alter microtubule-kinetochore attachment and invoke the mitotic checkpoint which arrests cells in mitosis. The arrest can last for hours, but it is leaky: cells adapt (i.e., slip out of it) and exit from mitosis. Here, we investigate the mechanism that allows cells to escape, and whether it is possible to prevent it. Based on a model of the mitotic checkpoint which includes the presence of a positive feedback loop, the escape from the arrest is described as a stochastic transition driven by fluctuations of molecular components from a checkpoint ON to a checkpoint OFF state. According to the model, drug removal further facilitates adaptation, a prediction we confirmed in budding yeast. The model suggests two ways to avoid adaptation: inhibition of APC/C and strengthening the mitotic checkpoint. We confirmed experimentally that both alterations decrease the chance of cells slipping out of mitosis, during a prolonged arrest and after washing out the drug. Our results may be relevant for increasing the efficiency of microtubule depolymerizing drugs.
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| Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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| Site | Modification | Modifier | Source | Reference |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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| Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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| Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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| Evidence ID | Analyze ID | File | Description |
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