Dataset Information

Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint.

ABSTRACT: The spindle assembly checkpoint arrests mitotic progression until each kinetochore secures a stable attachment to the spindle. Despite fluctuating noise, this checkpoint remains robust and remarkably sensitive to even a single unattached kinetochore among many attached kinetochores; moreover, the checkpoint is silenced only after the final kinetochore-spindle attachment. Experimental observations have shown that checkpoint components stream from attached kinetochores along microtubules towards spindle poles. Here we incorporate this streaming behaviour into a theoretical model that accounts for the robustness of checkpoint silencing. Poleward streams are integrated at spindle poles, but are diverted by any unattached kinetochore; consequently, accumulation of checkpoint components at spindle poles increases markedly only when every kinetochore is properly attached. This step change robustly triggers checkpoint silencing after, and only after, the final kinetochore-spindle attachment. Our model offers a conceptual framework that highlights the role of spatiotemporal regulation in mitotic spindle checkpoint signalling and fidelity of chromosome segregation.

SUBMITTER: Chen J

PROVIDER: S-EPMC4163959 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint.

Chen Jing J Liu Jian J

Nature communications 20140912

The spindle assembly checkpoint arrests mitotic progression until each kinetochore secures a stable attachment to the spindle. Despite fluctuating noise, this checkpoint remains robust and remarkably sensitive to even a single unattached kinetochore among many attached kinetochores; moreover, the checkpoint is silenced only after the final kinetochore-spindle attachment. Experimental observations have shown that checkpoint components stream from attached kinetochores along microtubules towards s ...[more]

PMID: 25216458

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Project description:To segregate chromosomes during cell division, microtubules that form the bipolar spindle attach to and pull on paired chromosome kinetochores. The spindle assembly checkpoint (SAC) is activated at unattached and misattached kinetochores to prevent further mitotic progression. The SAC is silenced after all the kinetochores establish proper and stable attachment to the spindle. Robust timing of SAC silencing after the last kinetochore-spindle attachment herein dictates the fidelity of chromosome segregation. Chromosome missegregation is rare in typical somatic cell mitosis, but frequent in cancer cell mitosis and in meiosis I of mammalian oocytes. In the latter cases, SAC is normally activated in response to disruptions of kinetochore-spindle attachments, suggesting that frequent chromosome missegregation ensues from faulty SAC silencing. In-depth understanding of how SAC silencing malfunctions in these cases is yet missing, but is believed to hold promise for treatment of cancer and prevention of human miscarriage and birth defects. We previously established a spatiotemporal model that, to the best of our knowledge, explained the robustness of SAC silencing in normal mitosis for the first time. In this article, we take advantage of the whole-cell perspective of the spatiotemporal model to identify possible causes of chromosome missegregation out of the distinct features of spindle assembly exhibited by cancer cells and mammalian oocytes. The model results explain why multipolar spindle could inhibit SAC silencing and spindle pole clustering could promote it-albeit accompanied by more kinetochore attachment errors. The model also eliminates geometric factors as the cause for nonrobust SAC silencing in oocyte meiosis, and instead, suggests atypical kinetochore-spindle attachment in meiosis as a potential culprit. Overall, the model shows that abnormal spindle-pole formation and its aberrant coordination with atypical kinetochore-spindle attachments could compromise the robustness of SAC silencing. Our model highlights systems-level coupling between kinetochore-spindle attachment and spindle-pole formation in SAC silencing.

Dataset Information

Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint.

Publications

Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint.

Similar Datasets

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