Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification

Mercadante, Dayna; Aaron, William A; Olson, Sarah D.; Manning, Amity L.

doi:10.1101/2022.08.04.502862

Cited by 4 publications

(4 citation statements)

References 87 publications

(130 reference statements)

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“…On the other hand, DDN can also localize to the mitotic cell cortex where it captures astral microtubules to control spindle positioning 15 . Cortical DDN may function for centrosome clustering in cooperation with pole-localized DDN in tetraploid cells, as reported recently 27 . Interestingly, NuMA is over-expressed in some cancer cells and elevated NuMA expression promotes the formation multipolar spindles in cancer cells with extra centrosomes 28 .…”

Section: Numa-mediated K-fiber Minus-end Clustering Is Required For P...supporting

confidence: 62%

NuMA deficiency causes micronuclei via checkpoint-insensitive k-fiber minus-end detachment from mitotic spindle poles

Toorn¹,

Gooch²,

Boerner³

et al. 2022

Preprint

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Micronuclei resulting from improper chromosome segregation foster chromosomal instability in somatic cell division cycles. To prevent micronuclei formation, bundled kinetochore-microtubules called k-fibers must be properly connected to all sister kinetochores on chromosomes via their plus-ends, whereas k-fiber minus-ends must be clustered at the two opposing spindle poles throughout mitosis. The bipolar attachment between sister kinetochores and k-fiber plus-ends is carefully monitored by the spindle assembly checkpoint and further promoted by error-correction mechanisms. However, how k-fiber minus-end clustering is maintained and monitored remains poorly understood. Here, we show that degradation of the Nuclear Mitotic Apparatus (NuMA) protein by auxin-inducible degron technologies in human cells results in micronuclei formation through k-fiber minus-end detachment from focused spindle poles during metaphase. Importantly, this k-fiber minus-end detachment creates misaligned chromosomes that maintain chromosome biorientation and do not activate the mitotic checkpoint, resulting in lagging chromosomes in anaphase. Moreover, we find that NuMA depletion causes centrosome clustering defects in tetraploid cells, leading to an increased frequency of multipolar divisions. Together, our data indicate that NuMA-mediated minus-end clustering of k-fibers and spindle microtubules is critical for faithful chromosome segregation. Similar to erroneous merotelic kinetochore attachments, detachment of k-fiber minus-ends from metaphase spindle poles evades spindle checkpoint surveillance and may therefore be a source of genomic instability in dividing cells.

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Section: Numa-mediated K-fiber Minus-end Clustering Is Required For P...supporting

confidence: 62%

NuMA deficiency causes micronuclei via checkpoint-insensitive k-fiber minus-end detachment from mitotic spindle poles

Toorn¹,

Gooch²,

Boerner³

et al. 2022

Preprint

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show abstract

“…This finding points out one functional role of exclusion of CSs from the cell center, especially by active mechanisms such as pulling by cortical dynein. This novel role contrasts with the established function of cortical dynein and cortical force in regulating spindle assembly, spindle positioning, and CS clustering in relation to the extracellular environment (Basto et al, 2008;Kiyomitsu and Cheeseman, 2012;Knouse et al, 2018;Mercadante et al, 2023).…”

Section: Discussionmentioning

confidence: 60%

A fine balance among key biophysical factors is required for recovery of bipolar mitotic spindle from monopolar and multipolar abnormalities

Bloomfield

Bridgeland

et al. 2023

MBoC

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During mitosis, equal partitioning of chromosomes into two daughter cells requires assembly of a bipolar mitotic spindle. Since the spindle poles are each organized by a centrosome in animal cells, centrosome defects can lead to abnormal, monopolar, or multipolar spindles. However, the cell can effectively recover the bipolar spindle by separating the centrosomes in monopolar spindles and clustering them in multipolar spindles. To interrogate how a cell can separate and cluster centrosomes as needed to form a bipolar spindle, we developed a biophysical model, based on experimental data, that uses effective potential energies to describe key mechanical forces driving centrosome movements during spindle assembly. Our model identified general biophysical factors crucial for robust bipolarization of spindles that start monopolar or multipolar. These factors include appropriate force fluctuation between centrosomes, balance between repulsive and attractive forces between centrosomes, exclusion of the centrosomes from the cell center, proper cell size and geometry, and a limited centrosome number. Consistently, we found experimentally that bipolar centrosome clustering is promoted as mitotic cell aspect ratio and volume decrease in tetraploid cancer cells. Our model provides mechanistic explanations for many more experimental phenomena and a useful theoretical framework for future studies of spindle assembly. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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“…While a nonuniform distribution of CFGs is important to spindle placement, we did not study it here. Such nonuniformity has been posited to explain clustering of centrosomes [54], and it would be interesting to understand what the the S-model predicts for aster arrangements in cells with non-uniform CFG distributions.…”

Section: Discussionmentioning

confidence: 99%

A first-principles geometric model for dynamics of motor-driven centrosomal asters

Young,

Gomez Herrera,

Huan

et al. 2024

Preprint

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The centrosomal aster is a mobile and adaptable cellular organelle that exerts and transmits forces necessary for tasks such as nuclear migration and spindle positioning. Recent experimental and theoretical studies of nematode and human cells demonstrate that pulling forces on asters by cortically anchored force generators are dominant during such processes. Here we present a comprehensive investigation of a first-principles model of aster dynamics, the S-model (S for stoichiometry), based solely on such forces. The model evolves the astral centrosome position, a probability field of cell-surface motor occupancy by centrosomal microtubules (under an assumption of stoichiometric binding), and free boundaries of unattached, growing microtubules. We show how cell shape affects the stability of centering of the aster, and its transition to oscillations with increasing motor number. Seeking to understand observations in single-cell nematode embryos, we use highly accurate simulations to examine the nonlinear structures of the bifurcations, and demonstrate the importance of binding domain overlap to interpreting genetic perturbation experiments. We find a generally rich dynamical landscape, dependent upon cell shape, such as internal constant-velocity equatorial orbits of asters that can be seen as traveling wave solutions. Finally, we study the interactions of multiple asters which we demonstrate an effective mutual repulsion due to their competition for surface force generators. We find, amazingly, that centrosomes can relax onto the vertices of platonic and non-platonic solids, very closely mirroring the results of the classical Thomson problem for energy-minimizing configurations of electrons constrained to a sphere and interacting via repulsive Coulomb potentials. Our findings both explain experimental observations, providing insights into the mechanisms governing spindle positioning and cell division dynamics, and show the possibility of new nonlinear phenomena in cell biology.

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Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification

Cited by 4 publications

References 87 publications

NuMA deficiency causes micronuclei via checkpoint-insensitive k-fiber minus-end detachment from mitotic spindle poles

NuMA deficiency causes micronuclei via checkpoint-insensitive k-fiber minus-end detachment from mitotic spindle poles

A fine balance among key biophysical factors is required for recovery of bipolar mitotic spindle from monopolar and multipolar abnormalities

A first-principles geometric model for dynamics of motor-driven centrosomal asters

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