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 Marija (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 NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Molecular Biology
Projects:	Project title Project leader Project code Project type Molecular origins of aneuploidies in healthy and diseased human tissues Tolić, Iva Marija; Pavin, Nenad 855158 EK Oscilatorna dinamika citoskeleta Tolić, Iva Marija IP-2014-09-4753 HRZZ A new class of microtubules in the spindle exerting forces on kinetochores Tolić, Iva Marija 647077 EK Provedba vrhunskih istraživanja u sklopu Znanstvenog centra izvrsnosti za kvantne i kompleksne sustave te reprezentacije Liejevih algebri-QuantiXLie Hrvoje Buljan; Pavle Pandžić KK.01.1.1.01.0004 EK
Depositing User:	Maša Sabo
Date Deposited:	20 May 2021 09:36
URI:	http://fulir.irb.hr/id/eprint/6400
DOI:	10.1016/j.devcel.2021.04.005

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