Unattached kinetochores rather than intrakinetochore tension arrest mitosis in taxol-treated cells

Magidson, Valentin; He, Jie; Ault, Jeffrey G.; O’Connell, Christopher B.; Yang, Nachen; Tikhonenko, Irina; McEwen, Bruce F.; Sui, Haixin; Khodjakov, Alexey

doi:10.1083/jcb.201412139

Cited by 64 publications

(108 citation statements)

References 40 publications

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“…It is also important to note here that the attachment-induced separation of two kinetochore proteins from one-another has sometimes been construed as “intra-kinetochore stretch”, and hence considered a tension-based mechanism [116,117,118]. However, physical separation of two mechanically unlinked protein domains does not necessarily require a large force.…”

Section: Directions For Future Investigations Of the Sacmentioning

confidence: 99%

A Cell Biological Perspective on Past, Present and Future Investigations of the Spindle Assembly Checkpoint

Joglekar¹

2016

Biology

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The spindle assembly checkpoint (SAC) is a quality control mechanism that ensures accurate chromosome segregation during cell division. It consists of a mechanochemical signal transduction mechanism that senses the attachment of chromosomes to the spindle, and a signaling cascade that inhibits cell division if one or more chromosomes are not attached. Extensive investigations of both these component systems of the SAC have synthesized a comprehensive understanding of the underlying molecular mechanisms. This review recounts the milestone results that elucidated the SAC, compiles a simple model of the complex molecular machinery underlying the SAC, and highlights poorly understood facets of the biochemical design and cell biological operation of the SAC that will drive research forward in the near future.

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Section: Directions For Future Investigations Of the Sacmentioning

confidence: 99%

A Cell Biological Perspective on Past, Present and Future Investigations of the Spindle Assembly Checkpoint

Joglekar¹

2016

Biology

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“…Many of these components contain inherently flexible domains and linkages [3]. Additionally, the microtubule plus-end likely re-organizes this protein network in a functionally significant manner [46, 47]. These issues pose a major obstacle for structural biological approaches in defining its architecture.…”

Section: The Protein Architecture In the End-on Kinetochore-microtubumentioning

confidence: 99%

How Kinetochore Architecture Shapes the Mechanisms of Its Function

Joglekar

Kukreja

2017

Current Biology

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The eukaryotic kinetochore is a sophisticated multi-protein machine that segregates chromosomes during cell division. To ensure accurate chromosome segregation, it performs three major functions using disparate molecular mechanisms. It operates a mechanosensitive signaling cascade known as the Spindle Assembly Checkpoint (SAC) to detect and signal the lack of attachment to spindle microtubules, and delay anaphase onset in response. After attaching to spindle microtubules, the kinetochore generates the force necessary to move chromosomes. Finally, if the two sister kinetochores on a chromosome are both attached to microtubules emanating from the same spindle pole, they activate another mechanosensitive mechanism to correct the monopolar attachments. All three functions maintain genome stability during cell division. The outlines of the biochemical activities responsible for these functions are now available. How the kinetochore integrates the underlying molecular mechanisms is still being elucidated. In this review, we will discuss how the nanoscale protein organization in the kinetochore, which we refer to as kinetochore ‘architecture’, organizes its biochemical activities to facilitate the realization and integration of emergent mechanisms underlying its three major functions. For this discussion, we will use the relatively simple budding yeast kinetochore as a model, and extrapolate insights gained from this model to elucidate functional roles of the architecture of the much more complex human kinetochore.

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“…The KNL1, Mis12, and Ndc80 subcomplexes can form a larger complex called the KMN network that has microtubule-binding activities [71,92]. The relative positions of these subcomplexes within kinetochores have been determined by super-resolution microscopy, revealing the overall protein architecture of kinetochores [93–95]. …”

Section: Conventional Kinetochoresmentioning

confidence: 99%

The unconventional kinetoplastid kinetochore: from discovery toward functional understanding

Akiyoshi

2016

Biochemical Society Transactions

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The kinetochore is the macromolecular protein complex that drives chromosome segregation in eukaryotes. Its most fundamental function is to connect centromeric DNA to dynamic spindle microtubules. Studies in popular model eukaryotes have shown that centromere protein (CENP)-A is critical for DNA-binding, whereas the Ndc80 complex is essential for microtubule-binding. Given their conservation in diverse eukaryotes, it was widely believed that all eukaryotes would utilize these components to make up a core of the kinetochore. However, a recent study identified an unconventional type of kinetochore in evolutionarily distant kinetoplastid species, showing that chromosome segregation can be achieved using a distinct set of proteins. Here, I review the discovery of the two kinetochore systems and discuss how their studies contribute to a better understanding of the eukaryotic chromosome segregation machinery.

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Unattached kinetochores rather than intrakinetochore tension arrest mitosis in taxol-treated cells

Abstract: Taxol induces extensive structural reorganization of the mammalian kinetochore; however, this reorganization is not sufficient to maintain a long-term mitotic arrest unless some of the kinetochores completely lose their attachment to microtubules.

Cited by 64 publications

References 40 publications

A Cell Biological Perspective on Past, Present and Future Investigations of the Spindle Assembly Checkpoint

A Cell Biological Perspective on Past, Present and Future Investigations of the Spindle Assembly Checkpoint

How Kinetochore Architecture Shapes the Mechanisms of Its Function

The unconventional kinetoplastid kinetochore: from discovery toward functional understanding

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