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Article ; Online: Chromosome size-dependent polar ejection force impairs mammalian mitotic error correction.

Chong, Megan K / Rosas-Salvans, Miquel / Tran, Vanna / Dumont, Sophie

2024 Volume 223, Issue 8

Abstract: Accurate chromosome segregation requires sister kinetochores to biorient, attaching to opposite spindle poles. To this end, the mammalian kinetochore destabilizes incorrect attachments and stabilizes correct ones, but how it discriminates between these ... ...

Abstract	Accurate chromosome segregation requires sister kinetochores to biorient, attaching to opposite spindle poles. To this end, the mammalian kinetochore destabilizes incorrect attachments and stabilizes correct ones, but how it discriminates between these is not yet clear. Here, we test the model that kinetochore tension is the stabilizing cue and ask how chromosome size impacts that model. We live image PtK2 cells, with just 14 chromosomes, widely ranging in size, and find that long chromosomes align at the metaphase plate later than short chromosomes. Enriching for errors and imaging error correction live, we show that long chromosomes exhibit a specific delay in correcting attachments. Using chromokinesin overexpression and laser ablation to perturb polar ejection forces, we find that chromosome size and force on arms determine alignment order. Thus, we propose a model where increased force on long chromosomes can falsely stabilize incorrect attachments, delaying their biorientation. As such, long chromosomes may require compensatory mechanisms for correcting errors to avoid chromosomal instability.
MeSH term(s)	Kinetochores/metabolism ; Mitosis ; Animals ; Chromosome Segregation ; Spindle Apparatus/metabolism ; Spindle Apparatus/genetics ; Cell Line ; Humans ; Chromosomes, Mammalian/metabolism ; Chromosomes, Mammalian/genetics
Language	English
Publishing date	2024-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202310010
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Article ; Online: Mechanisms underlying spindle assembly and robustness.

Valdez, Venecia A / Neahring, Lila / Petry, Sabine / Dumont, Sophie

Nature reviews. Molecular cell biology

2023 Volume 24, Issue 8, Page(s) 523–542

Abstract: The microtubule-based spindle orchestrates chromosome segregation during cell division. Following more than a century of study, many components and pathways contributing to spindle assembly have been described, but how the spindle robustly assembles ... ...

Abstract	The microtubule-based spindle orchestrates chromosome segregation during cell division. Following more than a century of study, many components and pathways contributing to spindle assembly have been described, but how the spindle robustly assembles remains incompletely understood. This process involves the self-organization of a large number of molecular parts - up to hundreds of thousands in vertebrate cells - whose local interactions give rise to a cellular-scale structure with emergent architecture, mechanics and function. In this Review, we discuss key concepts in our understanding of spindle assembly, focusing on recent advances and the new approaches that enabled them. We describe the pathways that generate the microtubule framework of the spindle by driving microtubule nucleation in a spatially controlled fashion and present recent insights regarding the organization of individual microtubules into structural modules. Finally, we discuss the emergent properties of the spindle that enable robust chromosome segregation.
MeSH term(s)	Spindle Apparatus/metabolism ; Microtubules/metabolism ; Cell Division ; Chromosome Segregation
Language	English
Publishing date	2023-03-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-023-00584-0
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Article: Chromosome size-dependent polar ejection force impairs mammalian mitotic error correction.

Chong, Megan K / Rosas-Salvans, Miquel / Tran, Vanna / Dumont, Sophie

bioRxiv : the preprint server for biology

2023

Abstract	Accurate chromosome segregation requires sister kinetochores to biorient, attaching to opposite spindle poles. To this end, the mammalian kinetochore destabilizes incorrect attachments and stabilizes correct ones, but how it discriminates between these is not yet clear. Here, we test the model that kinetochore tension is the stabilizing cue and ask how chromosome size impacts that model. We live image PtK2 cells, with just 14 chromosomes, widely ranging in size, and find that long chromosomes align at the metaphase plate later than short chromosomes. Enriching for errors and imaging error correction live, we show that long chromosomes exhibit a specific delay in correcting attachments. Using chromokinesin overexpression and laser ablation to perturb polar ejection forces, we find that chromosome size and force on arms determine alignment order. Thus, we propose a model where increased force on long chromosomes can falsely stabilize incorrect attachments, delaying their biorientation. As such, long chromosomes may require compensatory mechanisms for correcting errors to avoid chromosomal instability.
Language	English
Publishing date	2023-10-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.16.562637
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Article ; Online: Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle.

Suresh, Pooja / Galstyan, Vahe / Phillips, Rob / Dumont, Sophie

eLife

2022 Volume 11

Abstract: During cell division, the spindle generates force to move chromosomes. In mammals, microtubule bundles called kinetochore-fibers (k-fibers) attach to and segregate chromosomes. To do so, k-fibers must be robustly anchored to the dynamic spindle. We ... ...

Abstract	During cell division, the spindle generates force to move chromosomes. In mammals, microtubule bundles called kinetochore-fibers (k-fibers) attach to and segregate chromosomes. To do so, k-fibers must be robustly anchored to the dynamic spindle. We previously developed microneedle manipulation to mechanically challenge k-fiber anchorage, and observed spatially distinct response features revealing the presence of heterogeneous anchorage (Suresh et al., 2020). How anchorage is precisely spatially regulated, and what forces are necessary and sufficient to recapitulate the k-fiber's response to force remain unclear. Here, we develop a coarse-grained k-fiber model and combine with manipulation experiments to infer underlying anchorage using shape analysis. By systematically testing different anchorage schemes, we find that forces solely at k-fiber ends are sufficient to recapitulate unmanipulated k-fiber shapes, but not manipulated ones for which lateral anchorage over a 3 μm length scale near chromosomes is also essential. Such anchorage robustly preserves k-fiber orientation near chromosomes while allowing pivoting around poles. Anchorage over a shorter length scale cannot robustly restrict pivoting near chromosomes, while anchorage throughout the spindle obstructs pivoting at poles. Together, this work reveals how spatially regulated anchorage gives rise to spatially distinct mechanics in the mammalian spindle, which we propose are key for function.
MeSH term(s)	Animals ; Spindle Apparatus/physiology ; Kinetochores ; Microtubules/physiology ; Cell Division ; Mammals ; Mitosis
Language	English
Publishing date	2022-11-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.79558
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Article ; Online: Spindle size: small droplets and a big step forward.

Dumont, Sophie

Current biology : CB

2014 Volume 24, Issue 3, Page(s) R116–8

Abstract: The spindle is a micron-scale structure that assembles from nanometer-sized tubulin building blocks. How does the spindle know what size to be? Changes in cytoplasmic volume are shown to be sufficient to modulate the size of the spindle. ...

Abstract	The spindle is a micron-scale structure that assembles from nanometer-sized tubulin building blocks. How does the spindle know what size to be? Changes in cytoplasmic volume are shown to be sufficient to modulate the size of the spindle.
MeSH term(s)	Animals ; Cell Division ; Cytoplasm/physiology ; Embryonic Development ; Female ; Male ; Spindle Apparatus/physiology
Language	English
Publishing date	2014-02-06
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2013.12.031
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Article ; Online: The Astrin-SKAP complex reduces friction at the kinetochore-microtubule interface.

Rosas-Salvans, Miquel / Sutanto, Renaldo / Suresh, Pooja / Dumont, Sophie

Current biology : CB

2022 Volume 32, Issue 12, Page(s) 2621–2631.e3

Abstract: The kinetochore links chromosomes to spindle microtubules to drive chromosome segregation at cell division. While we know nearly all mammalian kinetochore proteins, how these give rise to the strong yet dynamic microtubule attachments required for ... ...

Abstract	The kinetochore links chromosomes to spindle microtubules to drive chromosome segregation at cell division. While we know nearly all mammalian kinetochore proteins, how these give rise to the strong yet dynamic microtubule attachments required for function remains poorly understood. Here, we focus on the Astrin-SKAP complex, which localizes to bioriented kinetochores and is essential for chromosome segregation but whose mechanical role is unclear. Live imaging reveals that SKAP depletion dampens the movement and decreases the coordination of metaphase sister kinetochores and increases the tension between them. Using laser ablation to isolate kinetochores bound to polymerizing versus depolymerizing microtubules, we show that without SKAP, kinetochores move slower on both polymerizing and depolymerizing microtubules and that more force is needed to rescue microtubules to polymerize. Thus, in contrast to the previously described kinetochore proteins that increase the grip on microtubules under force, Astrin-SKAP reduces the grip, increasing attachment dynamics and force responsiveness and reducing friction. Together, our findings suggest a model where the Astrin-SKAP complex effectively "lubricates" correct, bioriented attachments to help preserve them.
MeSH term(s)	Alcian Blue ; Animals ; Cell Cycle Proteins/metabolism ; Chromosome Segregation ; Friction ; Kinetochores/metabolism ; Mammals/genetics ; Microtubule-Associated Proteins/metabolism ; Microtubules/metabolism ; Mitosis ; Phenazines ; Phenothiazines ; Resorcinols ; Spindle Apparatus/metabolism
Chemical Substances	Cell Cycle Proteins ; Microtubule-Associated Proteins ; Phenazines ; Phenothiazines ; Resorcinols ; astrin (83097-09-0) ; Alcian Blue (P4448TJR7J)
Language	English
Publishing date	2022-05-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2022.04.061
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Article ; Online: Kinetochore-fiber lengths are maintained locally but coordinated globally by poles in the mammalian spindle.

Richter, Manuela / Neahring, Lila / Tao, Jinghui / Sutanto, Renaldo / Cho, Nathan H / Dumont, Sophie

eLife

2023 Volume 12

Abstract: At each cell division, nanometer-scale components self-organize to build a micron-scale spindle. In mammalian spindles, microtubule bundles called kinetochore-fibers attach to chromosomes and focus into spindle poles. Despite evidence suggesting that ... ...

Abstract	At each cell division, nanometer-scale components self-organize to build a micron-scale spindle. In mammalian spindles, microtubule bundles called kinetochore-fibers attach to chromosomes and focus into spindle poles. Despite evidence suggesting that poles can set spindle length, their role remains poorly understood. In fact, many species do not have spindle poles. Here, we probe the pole's contribution to mammalian spindle length, dynamics, and function by inhibiting dynein to generate spindles whose kinetochore-fibers do not focus into poles, yet maintain a metaphase steady-state length. We find that unfocused kinetochore-fibers have a mean length indistinguishable from control, but a broader length distribution, and reduced length coordination between sisters and neighbors. Further, we show that unfocused kinetochore-fibers, like control, can grow back to their steady-state length if acutely shortened by drug treatment or laser ablation: they recover their length by tuning their end dynamics, albeit slower due to their reduced baseline dynamics. Thus, kinetochore-fiber dynamics are regulated by their length, not just pole-focusing forces. Finally, we show that spindles with unfocused kinetochore-fibers can segregate chromosomes but fail to correctly do so. We propose that mammalian spindle length emerges locally from individual k-fibers while spindle poles globally coordinate k-fibers across space and time.
MeSH term(s)	Animals ; Kinetochores ; Microtubules ; Metaphase ; Cell Division ; Mammals ; Spindle Apparatus
Language	English
Publishing date	2023-07-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.85208
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Article ; Online: Mammalian kinetochores count attached microtubules in a sensitive and switch-like manner.

Kuhn, Jonathan / Dumont, Sophie

The Journal of cell biology

2019 Volume 218, Issue 11, Page(s) 3583–3596

Abstract: The spindle assembly checkpoint (SAC) prevents anaphase until all kinetochores attach to the spindle. Each mammalian kinetochore binds many microtubules, but how many attached microtubules are required to turn off the checkpoint, and how the kinetochore ... ...

Abstract	The spindle assembly checkpoint (SAC) prevents anaphase until all kinetochores attach to the spindle. Each mammalian kinetochore binds many microtubules, but how many attached microtubules are required to turn off the checkpoint, and how the kinetochore monitors microtubule numbers, are not known and are central to understanding SAC mechanisms and function. To address these questions, here we systematically tune and fix the fraction of Hec1 molecules capable of microtubule binding. We show that Hec1 molecules independently bind microtubules within single kinetochores, but that the kinetochore does not independently process attachment information from different molecules. Few attached microtubules (20% occupancy) can trigger complete Mad1 loss, and Mad1 loss is slower in this case. Finally, we show using laser ablation that individual kinetochores detect changes in microtubule binding, not in spindle forces that accompany attachment. Thus, the mammalian kinetochore responds specifically to the binding of each microtubule and counts microtubules as a single unit in a sensitive and switch-like manner. This may allow kinetochores to rapidly react to early attachments and maintain a robust SAC response despite dynamic microtubule numbers.
MeSH term(s)	HeLa Cells ; Humans ; Kinetochores/metabolism ; Microtubules/metabolism ; Tumor Cells, Cultured
Language	English
Publishing date	2019-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201902105
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Article: The oncogene cyclin D1 promotes bipolar spindle integrity under compressive force.

Sutanto, Renaldo / Neahring, Lila / Marques, Andrea Serra / Kilinc, Seda / Goga, Andrei / Dumont, Sophie

bioRxiv : the preprint server for biology

2023

Abstract: The mitotic spindle is the bipolar, microtubule-based structure that segregates chromosomes at each cell division. Aberrant spindles are frequently observed in cancer cells, but how oncogenic transformation affects spindle mechanics and function, ... ...

Abstract	The mitotic spindle is the bipolar, microtubule-based structure that segregates chromosomes at each cell division. Aberrant spindles are frequently observed in cancer cells, but how oncogenic transformation affects spindle mechanics and function, particularly in the mechanical context of solid tumors, remains poorly understood. Here, we constitutively overexpress the oncogene cyclin D1 in human MCF10A cells to probe its effects on spindle architecture and response to compressive force. We find that cyclin D1 overexpression increases the incidence of spindles with extra poles, centrioles, and chromosomes. However, it also protects spindle poles from fracturing under compressive force, a deleterious outcome linked to multipolar cell divisions. Our findings suggest that cyclin D1 overexpression may adapt cells to increased compressive stress, contributing to its prevalence in cancers such as breast cancer by allowing continued proliferation in mechanically challenging environments.
Language	English
Publishing date	2023-05-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.30.542893
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Article ; Online: The oncogene cyclin D1 promotes bipolar spindle integrity under compressive force.

Sutanto, Renaldo / Neahring, Lila / Serra Marques, Andrea / Jacobo Jacobo, Mauricio / Kilinc, Seda / Goga, Andrei / Dumont, Sophie

PloS one

2024 Volume 19, Issue 3, Page(s) e0296779

Abstract	The mitotic spindle is the bipolar, microtubule-based structure that segregates chromosomes at each cell division. Aberrant spindles are frequently observed in cancer cells, but how oncogenic transformation affects spindle mechanics and function, particularly in the mechanical context of solid tumors, remains poorly understood. Here, we constitutively overexpress the oncogene cyclin D1 in human MCF10A cells to probe its effects on spindle architecture and response to compressive force. We find that cyclin D1 overexpression increases the incidence of spindles with extra poles, centrioles, and chromosomes. However, it also protects spindle poles from fracturing under compressive force, a deleterious outcome linked to multipolar cell divisions. Our findings suggest that cyclin D1 overexpression may adapt cells to increased compressive stress, possibly contributing to its prevalence in cancers such as breast cancer by allowing continued proliferation in mechanically challenging environments.
MeSH term(s)	Humans ; Centrioles ; Centrosome ; Cyclin D1/genetics ; Mitosis ; Oncogenes ; Spindle Apparatus/genetics
Chemical Substances	Cyclin D1 (136601-57-5) ; CCND1 protein, human
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0296779
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