Structural plasticity of the living kinetochore

Dhatchinamoorthy, Karthik; Shivaraju, Manjunatha; Lange, Jeffrey J.; Rubinstein, Boris; Unruh, Jay R.; Slaughter, Brian D.; Gerton, Jennifer L.

doi:10.1083/jcb.201703152

Cited by 45 publications

(77 citation statements)

References 83 publications

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“…If two Cse4 molecules are in the nucleosome, presumably two Okp1/Ame1 entities are bound, raising the question of the stoichiometry of other Ctf19 components relative to Okp1/Ame1. Of note, Okp1 and Ame1 are more abundant in the nucleus than Ctf19 and Mcm21 (Dhatchinamoorthy et al, 2017), arguing that not all cellular Okp1/Ame1 is part of COMA. Thus, further work is required to elucidate the precise architecture of the kinetochore at its interface with chromatin.…”

Section: Discussionmentioning

confidence: 95%

“…The Cse4 content has been proposed to oscillate during mitosis from one to two molecules per centromeric nucleosome (Shivaraju et al, 2012), whereas another study observed replacement of Cse4 during S-phase, and it remained stably present at the centromere for the rest of the cell cycle until the next S-phase (Wisniewski et al, 2014). Of note, Okp1 and Ame1 are more abundant in the nucleus than Ctf19 and Mcm21 (Dhatchinamoorthy et al, 2017), arguing that not all cellular Okp1/Ame1 is part of COMA. Of note, Okp1 and Ame1 are more abundant in the nucleus than Ctf19 and Mcm21 (Dhatchinamoorthy et al, 2017), arguing that not all cellular Okp1/Ame1 is part of COMA.…”

Section: Discussionmentioning

confidence: 98%

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The kinetochore module Okp1 ^CENP‐Q /Ame1 ^CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 ^CENP‐A

et al. 2018

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Kinetochores are supramolecular assemblies that link centromeres to microtubules for sister chromatid segregation in mitosis. For this, the inner kinetochore CCAN/Ctf19 complex binds to centromeric chromatin containing the histone variant CENP‐A, but whether the interaction of kinetochore components to centromeric nucleosomes is regulated by posttranslational modifications is unknown. Here, we investigated how methylation of arginine 37 (R37Me) and acetylation of lysine 49 (K49Ac) on the CENP‐A homolog Cse4 from Saccharomyces cerevisiae regulate molecular interactions at the inner kinetochore. Importantly, we found that the Cse4 N‐terminus binds with high affinity to the Ctf19 complex subassembly Okp1/Ame1 (CENP‐Q/CENP‐U in higher eukaryotes), and that this interaction is inhibited by R37Me and K49Ac modification on Cse4. In vivo defects in cse4‐R37A were suppressed by mutations in OKP1 and AME1, and biochemical analysis of a mutant version of Okp1 showed increased affinity for Cse4. Altogether, our results demonstrate that the Okp1/Ame1 heterodimer is a reader module for posttranslational modifications on Cse4, thereby targeting the yeast CCAN complex to centromeric chromatin.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

The kinetochore module Okp1 ^CENP‐Q /Ame1 ^CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 ^CENP‐A

et al. 2018

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“…The outer kinetochore forms the primary MT attachment site for the chromosomes through the KMN (or in yeast, MIND) networks/complexes [21,108,[166][167][168][169][170]. This network/complex contains the Ndc80, KNL1, Mis12, and Dam/DASH proteins/complexes, and is also important for kinetochore signaling and lost kinetochore recapture [77,110,171]. Chromosomes and kinetochores also contain Aurora B kinase (Ark1 in S. pombe), an essential spindle checkpoint component.…”

Section: A16 Chromosomesmentioning

confidence: 99%

Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling

Edelmaier

Lamson

Gergely

et al. 2019

Preprint

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The essential functions required for mitotic spindle assembly and chromosome biorientation and segregation are not fully understood, despite extensive study. To illuminate the combinations of ingredients most important to align and segregate chromosomes and simultaneously assemble a bipolar spindle, we developed a computational model of fission-yeast mitosis. Robust chromosome biorientation requires progressive restriction of attachment geometry, destabilization of misaligned attachments, and attachment force dependence. Large spindle length fluctuations can occur when the kinetochore-microtubule attachment lifetime is long. The primary spindle force generators are kinesin-5 motors and crosslinkers in early mitosis, while interkinetochore stretch becomes important after biorientation. The same mechanisms that contribute to persistent biorientation lead to segregation of chromosomes to the poles after anaphase onset. This model therefore provides a framework to interrogate key requirements for robust chromosome biorientation, spindle length regulation, and force generation in the spindle.

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“…For example, chromosome misalignment generates a signal that causes the DNA-bound kinetochore assembly platform to solidify while weakening the connection between the microtubule and its interacting proteins (Akiyoshi et al, 2013;Cheeseman et al, 2006;DeLuca et al, 2006;Kim and Yu, 2015;Pinsky et al, 2006). During anaphase, when microtubules pull sister chromatids to opposite spindle poles, outer kinetochore proteins are enriched, ensuring a persistent connection to the depolymerizing filament (Dhatchinamoorthy et al, 2017;Gascoigne and Cheeseman, 2013).…”

Section: Introductionmentioning

confidence: 99%

The structural basis for kinetochore stabilization by Cnn1/CENP-T

Hinshaw

2020

Preprint

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Chromosome segregation depends on a regulated connection between spindle microtubules and centromeric DNA. The kinetochore, a massive modular protein assembly, mediates this connection and also serves as a signaling hub that integrates and responds to changing cues during the cell cycle. Kinetochore functions evolve as the cell cycle progresses, culminating in the assurance of a persistent chromosome-microtubule connection during anaphase, when sister chromatids must transit into daughter cells uninterrupted. We previously determined the structure of the Ctf19 complex, a group of kinetochore proteins at the centromeric base of the kinetochore. We now present a high-resolution structure of a Ctf19 complex sub-assembly involved in centromere-microtubule contact: the Ctf3 complex bound to the Cnn1-Wip1 heterodimer. The resulting composite model of the Ctf19 complex and live-cell imaging experiments provide a mechanism for Cnn1-Wip1 recruitment to the kinetochore. The mechanism suggests feedback regulation of Ctf19 complex assembly and unanticipated similarities in kinetochore organization between yeast and vertebrates.

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Structural plasticity of the living kinetochore

Cited by 45 publications

References 83 publications

The kinetochore module Okp1 ^CENP‐Q /Ame1 ^CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 ^CENP‐A

The kinetochore module Okp1 ^CENP‐Q /Ame1 ^CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 ^CENP‐A

Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling

The structural basis for kinetochore stabilization by Cnn1/CENP-T

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Structural plasticity of the living kinetochore

Cited by 45 publications

References 83 publications

The kinetochore module Okp1 CENP‐Q /Ame1 CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 CENP‐A

The kinetochore module Okp1 CENP‐Q /Ame1 CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 CENP‐A

Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling

The structural basis for kinetochore stabilization by Cnn1/CENP-T

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The kinetochore module Okp1 ^CENP‐Q /Ame1 ^CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 ^CENP‐A

The kinetochore module Okp1 ^CENP‐Q /Ame1 ^CENP‐U is a reader for N‐terminal modifications on the centromeric histone Cse4 ^CENP‐A