The Ska complex promotes Aurora B activity to ensure chromosome biorientation

Redli, Patrick M.; Gasic, Ivana; Meraldi, Patrick; Nigg, Erich A.; Santamaría, Anna

doi:10.1083/jcb.201603019

Cited by 40 publications

(54 citation statements)

References 77 publications

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“…In human cells, deletion of the microtubule-binding domain of Ska1 does not prevent kinetochore localization, although it appears reduced (Redli et al, 2016; Schmidt et al, 2012). The human Ska complex has an additional subunit (Ska2), is hexameric ( C. elegans SKA complex is trimeric), and the Ska3 subunits are significantly divergent.…”

Section: Discussionmentioning

confidence: 99%

“…While robust biochemical association of purified recombinant human Ska and Ndc80 complexes has not been reported to date, this possibility is supported by localization of Ska to kinetochores lacking microtubule attachments following Aurora B kinase inhibition in human cells (Chan et al, 2012). The microtubule-binding domain of human Ska1 has also been suggested to bind protein phosphatase 1 (Sivakumar et al, 2016) and to bind and activate Aurora B (Redli et al, 2016). We have not observed reduction in protein phosphatase 1 (GSP-2) localization at kinetochores or phenotypes associated with reduced Aurora B activity in ska-1Δ ( not shown ), suggesting that these proposed interactions are not conserved in C. elegans .…”

Section: Discussionmentioning

confidence: 99%

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Dephosphorylation of the Ndc80 Tail Stabilizes Kinetochore-Microtubule Attachments via the Ska Complex

et al. 2017

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SUMMARY During cell division, genome inheritance is orchestrated by microtubule attachments formed at kinetochores of mitotic chromosomes. The primary microtubule coupler at the kinetochore, the Ndc80 complex, is regulated by Aurora kinase phosphorylation of its N-terminal tail. Dephosphorylation is proposed to stabilize kinetochore-microtubule attachments by strengthening electrostatic interactions of the tail with the microtubule lattice. Here, we show that removal of the Ndc80 tail, which compromises in vitro microtubule binding, has no effect on kinetochore-microtubule attachments in the C. elegans embryo. Despite this, preventing Aurora phosphorylation of the tail results in prematurely stable attachments that restrain spindle elongation. This premature stabilization requires the conserved microtubule-binding Ska complex, which enriches at attachment sites prior to anaphase onset to dampen chromosome motion. We propose that Ndc80 tail dephosphorylation promotes stabilization of kinetochore-microtubule attachments via the Ska complex and that this mechanism ensures accurate segregation by constraining chromosome motion following biorientation on the spindle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dephosphorylation of the Ndc80 Tail Stabilizes Kinetochore-Microtubule Attachments via the Ska Complex

et al. 2017

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“…The Aurora B kinase phosphorylates the SKA and Dam1 complexes to reduce their binding affinity for kinetochores [264,265,266,267], in line with a regulatory scheme that identifies the Aurora B kinase as a negative regulator of the strength of the attachment of kinetochores to microtubules, and as a crucial actor in the correction of improper kinetochore-microtubule attachments (see reviews by Lampson and Grishchuk and by Asbury and colleagues [14,30]). In a recent twist, the SKA complex was also shown to stimulate Aurora B activity [268]. …”

Section: The Outer Kinetochorementioning

confidence: 99%

A Molecular View of Kinetochore Assembly and Function

Musacchio

Desai

2017

Biology

484

589

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Kinetochores are large protein assemblies that connect chromosomes to microtubules of the mitotic and meiotic spindles in order to distribute the replicated genome from a mother cell to its daughters. Kinetochores also control feedback mechanisms responsible for the correction of incorrect microtubule attachments, and for the coordination of chromosome attachment with cell cycle progression. Finally, kinetochores contribute to their own preservation, across generations, at the specific chromosomal loci devoted to host them, the centromeres. They achieve this in most species by exploiting an epigenetic, DNA-sequence-independent mechanism; notable exceptions are budding yeasts where a specific sequence is associated with centromere function. In the last 15 years, extensive progress in the elucidation of the composition of the kinetochore and the identification of various physical and functional modules within its substructure has led to a much deeper molecular understanding of kinetochore organization and the origins of its functional output. Here, we provide a broad summary of this progress, focusing primarily on kinetochores of humans and budding yeast, while highlighting work from other models, and present important unresolved questions for future studies.

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“…In addition, although the Ska1 MTBD is necessary and sufficient for Ska1 complex microtubule binding and spindle localization [2], we note that recent work has also suggested a contribution to microtubule interactions from Ska3 [28]. Ultimately, these activities must be regulated [13, 29, 30] and integrated with other players at the kinetochore, including the Ndc80 complex [2, 31, 32], to ensure faithful chromosome segregation during every cell division.…”

Section: Resultsmentioning

confidence: 99%

Microtubule Tip Tracking by the Spindle and Kinetochore Protein Ska1 Requires Diverse Tubulin-Interacting Surfaces

et al. 2017

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Summary The macromolecular kinetochore functions to generate interactions between chromosomal DNA and spindle microtubules [1]. To facilitate chromosome movement and segregation, kinetochores must maintain associations with both growing and shrinking microtubule ends. It is critical to define the proteins and their properties that allow kinetochores to associate with dynamic microtubules. The kinetochore-localized human Ska1 complex binds to microtubules and tracks with depolymerizing microtubule ends [2]. We now demonstrate that the Ska1 complex also autonomously tracks with growing microtubule ends in vitro, a key property that would allow this complex to act at kinetochores to mediate persistent associations with dynamic microtubules. To define the basis for Ska1 complex interactions with dynamic microtubules, we investigated the tubulin-binding properties of the Ska1 microtubule binding domain. In addition to binding to the microtubule lattice and dolastatin-induced protofilament-like structures, we demonstrate that the Ska1 microtubule binding domain can associate with soluble tubulin heterodimers and promote assembly of oligomeric ring-like tubulin structures. We generated mutations on distinct surfaces of the Ska1 microtubule binding domain that disrupt binding to soluble tubulin, but do not prevent microtubule binding. These mutants display compromised microtubule tracking activity in vitro and result in defective chromosome alignment and mitotic progression in cells using a CRISPR/Cas9-based replacement assay. Our work supports a model in which multiple surfaces of Ska1 interact with diverse tubulin substrates to associate with dynamic microtubule polymers and facilitate optimal chromosome segregation.

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The Ska complex promotes Aurora B activity to ensure chromosome biorientation

Cited by 40 publications

References 77 publications

Dephosphorylation of the Ndc80 Tail Stabilizes Kinetochore-Microtubule Attachments via the Ska Complex

Dephosphorylation of the Ndc80 Tail Stabilizes Kinetochore-Microtubule Attachments via the Ska Complex

A Molecular View of Kinetochore Assembly and Function

Microtubule Tip Tracking by the Spindle and Kinetochore Protein Ska1 Requires Diverse Tubulin-Interacting Surfaces

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