Dynein prevents erroneous kinetochore-microtubule attachments in mitosis

Barišić, Marin; Maiato, Hélder

doi:10.1080/15384101.2015.1089369

Cited by 20 publications

(19 citation statements)

References 54 publications

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“…This work further demonstrated that kinetochore Dynein activity is dominant over PEFs along chromosome arms and this is required for poleward motion after initial lateral kinetochore-microtubule attachments. This role of Dynein prevents random chromosome ejection and stabilization of end-on kinetochore-microtubule attachments on chromosomes positioned near the poles due to the action of PEFs along chromosome arms, while bringing chromosomes close to the highest Aurora A activity near the poles [6,7,77,316]. This explains why “centrophilic” chromosomes after perturbation of CENP-E function move abnormally close to the pole and are mostly devoid of end-on attached microtubules [297,298] and lack any detectable oscillatory motion [295,297].…”

Section: Mechanisms Of Chromosome Congressionmentioning

confidence: 99%

“…This explains why “centrophilic” chromosomes after perturbation of CENP-E function move abnormally close to the pole and are mostly devoid of end-on attached microtubules [297,298] and lack any detectable oscillatory motion [295,297]. Overall, Dynein activity was proposed to prevent the formation of premature/erroneous kinetochore-microtubule attachments, thereby allowing CENP-E to undergo processive motion necessary to transport polar chromosomes along pre-existing spindle microtubules towards the equator [6,316]. …”

Section: Mechanisms Of Chromosome Congressionmentioning

confidence: 99%

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Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

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170

176

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Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.

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Section: Mechanisms Of Chromosome Congressionmentioning

confidence: 99%

Section: Mechanisms Of Chromosome Congressionmentioning

confidence: 99%

Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

Self Cite

170

176

View full text Add to dashboard Cite

show abstract

“…The major kinetochore-associated force producers at this stage are the plus-end-directed centromere protein (CENP)-E and the minus-end-directed dynein each of which are capable of producing forces in the low pN range (∼1–8 pNs)1234. While motor-mediated forces produced during lateral kt–MT interactions facilitate proper chromosome congression56, they are neither sufficient to satisfy the spindle assembly checkpoint nor to support accurate chromosome segregation during mitosis7. Rather, these outcomes require the formation of stable end-on kt–MT attachments that are mediated by a conserved MT-binding complex in the outer kinetochore called the KMN (KNL-1, Mis12 complex, Ndc80 complex) network8.…”

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confidence: 99%

Chromosome biorientation produces hundreds of piconewtons at a metazoan kinetochore

Cane

Maresca

2016

Nat Commun

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High-fidelity transmission of the genome through cell division requires that all sister kinetochores bind to dynamic microtubules (MTs) from opposite spindle poles. The application of opposing forces to this bioriented configuration produces tension that stabilizes kinetochore–microtubule (kt–MT) attachments. Defining the magnitude of force that is applied to kinetochores is central to understanding the mechano-molecular underpinnings of chromosome segregation; however, existing kinetochore force measurements span orders of magnitude. Here we measure kinetochore forces by engineering two calibrated force sensors into the Drosophila kinetochore protein centromere protein (CENP)-C. Measurements of both reporters indicate that they are, on average, under ∼1–2 piconewtons (pNs) of force at metaphase. Based on estimates of the number of CENP-C molecules and MTs per Drosophila kinetochore and envisioning kinetochore linkages arranged such that they distribute forces across them, we propose that kinetochore fibres (k-fibres) exert hundreds of pNs of poleward-directed force to bioriented kinetochores.

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“…However, in smaller mitotic cells such as HeLa where the chromosomes are separated only by smaller distances for the spindle poles (usually within 5-10 µms), we surmise that the disengagement of dynein/spindly from Rod and Ndc80 is a major cause of chromosome misalignment after dynein-or spindly-depletion, due to which Rod is able to impart a sustained inhibition of Ndc80 function. It is also possible that the polar ejection forces on chromosome arms produced by the MT plus-end-directed chromokinesin motors drive the chromosomes away from the spindle poles during early mitosis in the absence of dynein or spindly to hinder proper chromosome alignment (4,47) (also see in Fig. 3).…”

Section: Defects In Chromosome Alignment Induced By Spindly or Dyneinmentioning

confidence: 99%

Antagonism between the dynein and Ndc80 complexes at kinetochores controls the stability of kinetochore-microtubule attachments during mitosis

Amin¹,

McKenney

Varma³

2018

Preprint

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Chromosome alignment and segregation during mitosis depends critically on kinetochoremicrotubule (kMT) attachments that are mediated by the function of the molecular motor cytoplasmic dynein, and the kinetochore microtubule (MT) binding complex, Ndc80. The RZZ (Rod-ZW10-Zwilch) complex is central to this coordination as it has an important role in dynein recruitment and has recently been reported to have a key function in the regulation of stable kMT attachment formation in C. elegans. However, the mechanism by which kMT attachments are controlled by the coordinated function of these protein complexes to drive chromosome motility during early mitosis is still unclear. In this manuscript, we provide evidence to show that Ndc80 and dynein directly antagonize each other's MT-binding. We also find that severe chromosome alignment defects induced by depletion of dynein, or the dynein adapter spindly, are rescued by codepletion of the RZZ component, Rod, in human cells. Interestingly, the rescue of chromosome alignments defects was independent of Rod function in activation of the spindle assembly checkpoint and was accompanied by a remarkable restoration of stable kMT attachments.Furthermore, rescue of chromosome alignment was critically dependent on the plus-end-directed motility of CENP-E, as cells codepleted of CENP-E along with Rod and dynein were unable to establish stable kMT attachments or align their chromosomes properly. Taken together, our findings support the idea that the dynein motor may control the function of the Ndc80 complex in stabilizing kMT attachments either directly by interfering with Ndc80-MT binding, and/or indirectly by modulating the Rod-mediated inhibition of Ndc80.peer-reviewed)

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Dynein prevents erroneous kinetochore-microtubule attachments in mitosis

Cited by 20 publications

References 54 publications

Mechanisms of Chromosome Congression during Mitosis

Mechanisms of Chromosome Congression during Mitosis

Chromosome biorientation produces hundreds of piconewtons at a metazoan kinetochore

Antagonism between the dynein and Ndc80 complexes at kinetochores controls the stability of kinetochore-microtubule attachments during mitosis

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