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

Autor: Renata Buđa, Kruno Vukušić, Patrik Risteski, Iva M. Tolić, Ivana Ponjavić
Jazyk: angličtina
Předmět:
Zdroj: Developmental cell
Developmental Cell
ISSN: 1534-5807
DOI: 10.1016/j.devcel.2021.04.005
Popis: Summary 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.
Graphical abstract
Highlights • Spindle elongation depends on the joint activity of EG5/kinesin-5 and PRC1 • PRC1-dependent KIF4A/kinesin-4 is crucial for elongation upon EG5 inhibition • EG5 and KIF4A together slide antiparallel microtubules during early anaphase • Spindle elongation block induces large chromosome segregation defects
Vukušić et al. demonstrate that spindle elongation in human cells is powered by joint activity of kinesin-5 and kinesin-4 through their role in antiparallel microtubule sliding. Without elongation chromosome segregation frequently fails, demonstrating its requirement for successful cell division.
Databáze: OpenAIRE