Abstract
The bipolar mitotic spindle drives accurate chromosome segregation by capturing the kinetochore and pulling each set of sister chromatids to the opposite poles. In this review, we describe recent findings on the multiple pathways leading to bipolar spindle formation in fission yeast and discuss these results from a broader perspective. The roles of three mitotic kinesins (Kinesin-5, Kinesin-6 and Kinesin-14) in spindle assembly are depicted, and how a group of microtubule-associated proteins, sister chromatid cohesion and the kinetochore collaborate with these motors is shown. We have paid special attention to the molecular pathways that render otherwise essential Kinesin-5 to become non-essential: how cells build bipolar mitotic spindles without the need for Kinesin-5 and where the alternate forces come from are considered. We highlight the force balance for bipolar spindle assembly and explain how outward and inward forces are generated by various ways, in which the proper fine-tuning of microtubule dynamics plays a crucial role. Overall, these new pathways have illuminated the remarkable plasticity and adaptability of spindle mechanics. Kinesin molecules are regarded as prospective targets for cancer chemotherapy and many specific inhibitors have been developed. However, several hurdles have arisen against their clinical implementation. This review provides insight into possible strategies to overcome these challenges.
Highlights
The bipolar mitotic spindle is a dynamic ensemble of core microtubule polymers and a cohort of microtubule-associated proteins (MAPs)
Initial genetic studies and recent more comprehensive analysis conducted in Aspergillus nidulans and Saccharomyces cerevisiae showed that lethal mutations in Kinesin-5 are rescued by simultaneous inactivation of genes encoding Kinesin-14 [20,21,22,23]
We have found that mutations in the genes encoding tubulins and five non-motor MAPs are tubulin), atb2 (α2-tubulin) and nda3 (β-tubulin) [41,42] (Table 1)
Summary
The bipolar mitotic spindle is a dynamic ensemble of core microtubule polymers and a cohort of microtubule-associated proteins (MAPs). The type 5 kinesin (Kinesin-5) was originally identified in Aspergillus nidulans as one of the mitotically arrested mutants (called bimC) [8] This kinesin belongs to the N-kinesin that moves on microtubules towards their plus ends. This motor forms homotetramers, thereby crosslinking and sliding apart antiparallel microtubules [9,10] During early mitosis, this process generates an outward pushing force towards two duplicated spindle poles (centrosomes in animal cells and the spindle pole bodies (SPBs) in fungi), which promotes centrosome/SPB separation, thereby establishing spindle bipolarity [11,12]. If not all, eukaryotes, Kinesin-5 (budding yeast Cin and Kip, fission yeast Cut, Aspergillus BimC, C. elegans BMK-1, Drosophila Klp61F, Xenopus Eg5 and human KIF11) is essential for mitosis, in which any means of its inactivation, e.g., chemical inhibition, genetic deletion or RNAi-mediated depletion, leads to the emergence of monopolar spindles, the failure of chromosome segregation and viability loss [8,13,14,15,16,17,18,19]
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