Non-centrosomal microtubules at kinetochores promote rapid chromosome biorientation during mitosis in human cells.
agent-based simulation
chromosome segregation
computational model
kinetochore
mitosis
spindle assembly
Journal
Current biology : CB
ISSN: 1879-0445
Titre abrégé: Curr Biol
Pays: England
ID NLM: 9107782
Informations de publication
Date de publication:
14 03 2022
14 03 2022
Historique:
received:
02
07
2021
revised:
23
11
2021
accepted:
06
01
2022
pubmed:
3
2
2022
medline:
12
4
2022
entrez:
2
2
2022
Statut:
ppublish
Résumé
Proper segregation of chromosomes during mitosis depends on "amphitelic attachments"-load-bearing connections of sister kinetochores to the opposite spindle poles via bundles of microtubules, termed as the "K-fibers." Current models of spindle assembly assume that K-fibers arise largely from stochastic capture of microtubules, which occurs at random times and locations and independently at sister kinetochores. We test this assumption by following the movements of all kinetochores in human cells and determine that most amphitelic attachments form synchronously at a specific stage of spindle assembly and within a spatially distinct domain. This biorientation domain is enriched in bundles of antiparallel microtubules, and perturbation of microtubule bundling changes the temporal and spatial dynamics of amphitelic attachment formation. Structural analyses indicate that interactions of kinetochores with microtubule bundles are mediated by non-centrosomal short microtubules that emanate from most kinetochores during early prometaphase. Computational analyses suggest that momentous molecular motor-driven interactions with antiparallel bundles rapidly convert these short microtubules into nascent K-fibers. Thus, load-bearing connections to the opposite spindle poles form simultaneously on sister kinetochores. In contrast to the uncoordinated sequential attachments of sister kinetochores expected in stochastic models of spindle assembly, our model envisions the formation of amphitelic attachments as a deterministic process in which the chromosomes connect with the spindle poles synchronously at a specific stage of spindle assembly and at a defined location determined by the spindle architecture. Experimental analyses of changes in the kinetochore behavior in cells with perturbed activity of molecular motors CenpE and dynein confirm the predictive power of the model.
Identifiants
pubmed: 35108523
pii: S0960-9822(22)00024-0
doi: 10.1016/j.cub.2022.01.013
pmc: PMC8930511
mid: NIHMS1771166
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1049-1063.e4Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM130234
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM130298
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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