Spindle Architectural Features Must Be Considered Along With Cell Size to Explain the Timing of Mitotic Checkpoint Silencing

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dc.contributor.authorBloomfield, Mathewen
dc.contributor.authorChen, Jingen
dc.contributor.authorCimini, Danielaen
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2021-06-01T14:49:03Zen
dc.date.available2021-06-01T14:49:03Zen
dc.date.issued2021-01-28en
dc.description.abstractMitosis proceeds through a defined series of events that is largely conserved, but the amount of time needed for their completion can vary in different cells and organisms. In many systems, mitotic duration depends on the time required to satisfy and silence the spindle assembly checkpoint (SAC), also known as the mitotic checkpoint. Because SAC silencing involves trafficking SAC molecules among kinetochores, spindle, and cytoplasm, the size and geometry of the spindle relative to cell volume are expected to affect mitotic duration by influencing the timing of SAC silencing. However, the relationship between SAC silencing, cell size, and spindle dimensions is unclear. To investigate this issue, we used four DLD-1 tetraploid (4N) clones characterized by small or large nuclear and cell size. We found that the small 4N clones had longer mitotic durations than the parental DLD-1 cells and that this delay was due to differences in their metaphase duration. Leveraging a previous mathematical model for spatiotemporal regulation of SAC silencing, we show that the difference in metaphase duration, i.e., SAC silencing time, can be explained by the distinct spindle microtubule densities and sizes of the cell, spindle, and spindle poles in the 4N clones. Lastly, we demonstrate that manipulating spindle geometry can alter mitotic and metaphase duration, consistent with a model prediction. Our results suggest that spindle size does not always scale with cell size in mammalian cells and cell size is not sufficient to explain the differences in metaphase duration. Only when a number of spindle architectural features are considered along with cell size can the kinetics of SAC silencing, and hence mitotic duration, in the different clones be explained.en
dc.description.notesThis work was partly funded by the Virginia Tech Center for Engineered Health, through seed funds to DC. Work in the Cimini lab was also supported by NSF grant MCB-1517506 and NIH grant R01GM140042 to DC. JC is supported by NIH (1R35GM138370) and startup funds from the Virginia Tech Department of Biological Sciences and College of Science.en
dc.description.sponsorshipVirginia Tech Center for Engineered Health; NSFNational Science Foundation (NSF) [MCB-1517506]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R35GM138370, R01GM140042]; Virginia Tech Department of Biological Sciences and College of Scienceen
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fphys.2020.596263en
dc.identifier.issn1664-042Xen
dc.identifier.other596263en
dc.identifier.pmid33584330en
dc.identifier.urihttp://hdl.handle.net/10919/103552en
dc.identifier.volume11en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmitosisen
dc.subjectcell sizeen
dc.subjectnuclear sizeen
dc.subjectmitotic spindleen
dc.subjectmitotic checkpointen
dc.subjecttetraploidyen
dc.subjectSACen
dc.titleSpindle Architectural Features Must Be Considered Along With Cell Size to Explain the Timing of Mitotic Checkpoint Silencingen
dc.title.serialFrontiers in Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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