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Ectopic activation of the Spindle Assembly Checkpoint reveals its biochemical design and physiological operation

Chu Chen, Ian P. Whitney, Anand Banerjee, Palak Sekhri, David M. Kern, Adrienne Fontan, John J. Tyson, Iain M. Cheeseman, View ORCID ProfileAjit P. Joglekar
doi: https://doi.org/10.1101/154054
Chu Chen
1Department of Biophysics, University of Michigan, Ann Arbor, MI 48109
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Ian P. Whitney
2Whitehead Institute for Biomedical Research, and Department of Biology, MIT, Nine Cambridge Center, Cambridge, MA 02142
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Anand Banerjee
3Department of Biological Sciences, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061
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Palak Sekhri
4Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109
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David M. Kern
2Whitehead Institute for Biomedical Research, and Department of Biology, MIT, Nine Cambridge Center, Cambridge, MA 02142
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Adrienne Fontan
4Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109
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John J. Tyson
3Department of Biological Sciences, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061
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Iain M. Cheeseman
2Whitehead Institute for Biomedical Research, and Department of Biology, MIT, Nine Cambridge Center, Cambridge, MA 02142
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Ajit P. Joglekar
1Department of Biophysics, University of Michigan, Ann Arbor, MI 48109
4Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109
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  • ORCID record for Ajit P. Joglekar
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Summary

Switch-like activation of the Spindle Assembly Checkpoint (SAC) is critical for accurate chromosome segregation during cell division. To determine the mechanisms that implement it, we engineered an ectopic, kinetochore-independent SAC activator, the “eSAC”. The eSAC stimulates the SAC signaling cascade by artificially dimerizing the Mps1 kinase domain and a cytosolic KNL1 phosphodomain, the signaling scaffold in the kinetochore. Quantitative analyses and mathematical modeling of the eSAC reveal that the recruitment of multiple SAC proteins by the KNL1 phosphodomain stimulates synergistic signaling, which enables a small number of KNL1 molecules produce a disproportionately strong anaphase-inhibitory signal. However, when multiple KNL1 molecules signal concurrently, they compete for a limited cellular pool of SAC proteins. This frustrates synergistic signaling and modulates signal output. Together, these mechanisms institute automatic gain control – inverse, non-linear scaling between the signal output per kinetochore and the unattached kinetochore number, and thus enact the SAC switch.

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Posted June 22, 2017.
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Ectopic activation of the Spindle Assembly Checkpoint reveals its biochemical design and physiological operation
Chu Chen, Ian P. Whitney, Anand Banerjee, Palak Sekhri, David M. Kern, Adrienne Fontan, John J. Tyson, Iain M. Cheeseman, Ajit P. Joglekar
bioRxiv 154054; doi: https://doi.org/10.1101/154054
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Ectopic activation of the Spindle Assembly Checkpoint reveals its biochemical design and physiological operation
Chu Chen, Ian P. Whitney, Anand Banerjee, Palak Sekhri, David M. Kern, Adrienne Fontan, John J. Tyson, Iain M. Cheeseman, Ajit P. Joglekar
bioRxiv 154054; doi: https://doi.org/10.1101/154054

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