Abstract
ABSTRACTHigh-fidelity chromosome segregation relies on proper microtubule regulation. Kinesin-8 has been shown to destabilise microtubules to reduce metaphase spindle length and chromosome movements in multiple species. XMAP215/chTOG polymerases catalyse microtubule growth for spindle assembly, elongation and kinetochore-microtubule attachment. Understanding of their biochemical activity has advanced, but little work directly addresses the functionality and interplay of these conserved factors. We utilised the synthetic lethality of fission yeast kinesin-8 (Klp5-Klp6) and XMAP215/chTOG (Dis1) to study their individual and overlapping roles. We found that the non-motor kinesin-8 tailbox is essential for mitotic function; mutation compromises plus-end-directed processivity. Klp5-Klp6 induces catastrophes to control microtubule length and, surprisingly, Dis1 collaborates with kinesin-8 to slow spindle elongation. Together, they enforce a maximum spindle length for a viable metaphase–anaphase transition and limit elongation during anaphase A to prevent lagging chromatids. Our work provides mechanistic insight into how kinesin-8 negatively regulates microtubules and how this functionally overlaps with Dis1 and highlights the importance of spindle length control in mitosis.
Highlights
The mitotic spindle is a complex, macromolecular structure that, subject to precise control, orchestrates the accurate segregation of chromosomes; aberrations in this process can lead to aneuploidy, a risk factor for cancer and various human diseases (Zhang et al, 2010; Hanahan and Weinberg, 2011)
High-fidelity chromosome segregation relies on proper microtubule regulation
We utilised the synthetic lethality of fission yeast kinesin-8 (Klp5-Klp6) and XMAP215/chTOG (Dis1) to study their individual and overlapping roles
Summary
The mitotic spindle is a complex, macromolecular structure that, subject to precise control, orchestrates the accurate segregation of chromosomes; aberrations in this process can lead to aneuploidy, a risk factor for cancer and various human diseases (Zhang et al, 2010; Hanahan and Weinberg, 2011). Microtubules (MTs) constitute the core of the spindle: dynamic, polar polymers (Weisenberg et al, 1968; Mitchison and Kirschner, 1984; Mitchison, 1993) that form a physical scaffold for the mitotic apparatus and recruit a vast array of MT-associated proteins (MAPs) to regulate their length and behaviour Among this ensemble of MAPs, the kinesin-8 family of motor proteins are remarkable in that they translocate along MTs towards plus-ends (Gupta et al, 2006; Mayr et al, 2007; Grissom et al, 2009; Lee et al, 2010; Erent et al, 2012) and promote MT destabilisation (Gupta et al, 2006; Varga et al, 2006; Mayr et al, 2007; Unsworth et al, 2008; Tischer et al, 2009). Three different homodimers constitute the kinesin-8 repertoire in human cells: Kif19A depolymerises MTs in ciliary length control (Niwa et al, 2012), Kif18B negatively regulates astral MT length and number (Lee et al, 2010; Stout et al, 2011; Tanenbaum et al, 2011) and Kif18A reduces spindle length (Mayr et al, 2007; Stumpff et al, 2008; Mayr et al, 2011) and suppresses kinetochore (KT)-MT dynamics for proper chromosome congression (Stumpff et al, 2008; Mayr et al, 2011; Weaver et al, 2011)
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