Coordinated Poleward Flux of Sister Kinetochore Fibers Drives Chromosome Alignment

Risteski, Patrik; Božan, Domagoj; Jagrić, Mihaela; Bosilj, Agneza; Pavin, Nenad; Tolić, Iva M.

doi:10.2139/ssrn.3942846

Cited by 2 publications

(2 citation statements)

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“…How the architecture of the non-kMT network and the biophysical properties (ability to withstand and respond to force (Yusko and Asbury 2014)) of the many motor and non-motor microtubule associated proteins within it dictate network mechanics is an open question. Answering these questions for the mammalian spindle will require probing the physical (Belmonte et al 2017, Oriola et al 2018) and molecular (Kajtez et al 2016, Elting et al 2017, Suresh et al 2020, Risteski et al 2021) basis of the anchoring network’s emergent properties, to which controlled mechanical (such as microneedle manipulation) and molecular perturbations (Jagrić et al 2021) as well as modeling approaches (Nedelec and Foethke 2007) will be key. Looking forward, experiments and modeling will also be useful in shedding light on the temporal dynamics of anchorage mechanics – for example, how the timescale of network relaxation relates to the kinetics of molecular turnover (Saxton et al 1984, Pamula et al 2019) and the manipulation protocol.…”

Section: Discussionmentioning

confidence: 99%

Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle

Suresh

Galstyan

Phillips

et al. 2022

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle

Suresh

Galstyan

Phillips

et al. 2022

Preprint

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“…Kinetochores that become stably aligned maintain their position within the metaphase plate by moving in an oscillatory manner around the equatorial plane [39,40]. The main mechanisms that maintain chromosome alignment in vertebrate cells include the regulation of k-fiber plus end dynamics by motors such as Kif18a/kinesin-8, sliding of bridging MTs, and the action of polar ejection forces (PEFs) [41][42][43][44][45][46], though the level of contribution of each mechanism is still unclear. The relationship between the mechanisms that drive chromosome congression to the mechanisms that maintain their alignment at the equator is also unclear [7].…”

Section: Oscillating At the Equator-maintenance Of Alignmentmentioning

confidence: 99%

Polar Chromosomes—Challenges of a Risky Path

Vukušić

Tolić

2022

Cells

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The process of chromosome congression and alignment is at the core of mitotic fidelity. In this review, we discuss distinct spatial routes that the chromosomes take to align during prometaphase, which are characterized by distinct biomolecular requirements. Peripheral polar chromosomes are an intriguing case as their alignment depends on the activity of kinetochore motors, polar ejection forces, and a transition from lateral to end-on attachments to microtubules, all of which can result in the delayed alignment of these chromosomes. Due to their undesirable position close to and often behind the spindle pole, these chromosomes may be particularly prone to the formation of erroneous kinetochore-microtubule interactions, such as merotelic attachments. To prevent such errors, the cell employs intricate mechanisms to preposition the spindle poles with respect to chromosomes, ensure the formation of end-on attachments in restricted spindle regions, repair faulty attachments by error correction mechanisms, and delay segregation by the spindle assembly checkpoint. Despite this protective machinery, there are several ways in which polar chromosomes can fail in alignment, mis-segregate, and lead to aneuploidy. In agreement with this, polar chromosomes are present in certain tumors and may even be involved in the process of tumorigenesis.

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Coordinated Poleward Flux of Sister Kinetochore Fibers Drives Chromosome Alignment

Cited by 2 publications

References 54 publications

Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle

Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle

Polar Chromosomes—Challenges of a Risky Path

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