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Microtubule-sliding modules based on kinesins EG5 and PRC1-dependent KIF4A drive human spindle elongation

Vukušić, Kruno; Ponjavić, Ivana; Buđa, Renata; Risteski, Patrik; Tolić, Iva M. (2021) Microtubule-sliding modules based on kinesins EG5 and PRC1-dependent KIF4A drive human spindle elongation. Developmental cell, 56 (9). 1253-1267e10. ISSN 1534-5807

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Abstract

Proper chromosome segregation into two future daughter cells requires the mitotic spindle to elongate in anaphase. However, although some candidate proteins are implicated in this process, the molecular mechanism that drives spindle elongation in human cells is unknown. Using combined depletion and inactivation assays together with CRISPR technology to explore redundancy between multiple targets, we discovered that the force-generating mechanism of spindle elongation consists of EG5/kinesin-5 together with the PRC1-dependent motor KIF4A/kinesin-4, with contribution from kinesin-6 and kinesin-8. Disruption of EG5 and KIF4A leads to total failure of chromosome segregation due to blocked spindle elongation, despite poleward chromosome motion. Tubulin photoactivation, stimulated emission depletion (STED), and expansion microscopy show that perturbation of both proteins impairs midzone microtubule sliding without affecting microtubule stability. Thus, two mechanistically distinct sliding modules, one based on a self-sustained and the other on a crosslinker-assisted motor, power the mechanism that drives spindle elongation in human cells.

Item Type: Article
Uncontrolled Keywords: mitosis ; anaphase ; spindle elongation ; motor proteins ; microtubule sliding ; functional redundancy ; anaphase B ; kinesins ; EG5/kinesin-5 ; KIF4A/kinesin-4 ;
Subjects: NATURAL SCIENCES > Biology
Divisions: Division of Molecular Biology
Projects:
Project titleProject leaderProject codeProject type
Molecular origins of aneuploidies in healthy and diseased human tissuesTolić, Iva Marija; Pavin, Nenad855158EK
Oscilatorna dinamika citoskeletaTolić, Iva MarijaIP-2014-09-4753HRZZ
A new class of microtubules in the spindle exerting forces on kinetochoresTolić, Iva Marija647077EK
Depositing User: Kruno Vukušić
Date Deposited: 12 May 2021 13:01
Last Modified: 10 Aug 2021 10:33
URI: http://fulir.irb.hr/id/eprint/6405
DOI: 10.1016/j.devcel.2021.04.005

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