期刊
EMBO JOURNAL
卷 39, 期 23, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020105432
关键词
kinesins; kinetochore; microtubules; mitosis; mitotic spindle
资金
- Danish Cancer Society Scientific Committee (KBVU) [R146-A9322]
- Lundbeck Foundation [R215-2015-4081]
- Novo Nordisk Foundation [NNF19OC0058504]
- European Research Council under the European Union's Horizon 2020 research and innovation program [681443]
Mitotic spindle microtubules (MTs) undergo continuous poleward flux, whose driving force and function in humans remain unclear. Here, we combined loss-of-function screenings with analysis of MT-dynamics in human cells to investigate the molecular mechanisms underlying MT-flux. We report that kinesin-7/CENP-E at kinetochores (KTs) is the predominant driver of MT-flux in early prometaphase, while kinesin-4/KIF4A on chromosome arms facilitates MT-flux during late prometaphase and metaphase. Both these activities work in coordination with kinesin-5/EG5 and kinesin-12/KIF15, and our data suggest that the MT-flux driving force is transmitted from non-KT-MTs to KT-MTs by the MT couplers HSET and NuMA. Additionally, we found that the MT-flux rate correlates with spindle length, and this correlation depends on the establishment of stable end-on KT-MT attachments. Strikingly, we find that MT-flux is required to regulate spindle length by counteracting kinesin 13/MCAK-dependent MT-depolymerization. Thus, our study unveils the long-sought mechanism of MT-flux in human cells as relying on the coordinated action of four kinesins to compensate for MT-depolymerization and regulate spindle length.
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