Abstract
What forces drive chromosome segregation remains one of the most challenging questions in cell division. Even though the duration of anaphase is short, it is of utmost importance for genome fidelity that no mistakes are made. Seminal studies in model organisms have revealed different mechanisms operating during chromosome segregation in anaphase, but the translation of these mechanisms to human cells is not straightforward. Recent work has shown that kinetochore fiber depolymerization during anaphase A is largely motor independent, whereas spindle elongation during anaphase B is coupled to sliding of interpolar microtubules in human cells. In this Review, we discuss the current knowledge on the mechanisms of force generation by kinetochore, interpolar and astral microtubules. By combining results from numerous studies, we propose a comprehensive picture of the role of individual force-producing and -regulating proteins. Finally, by linking key concepts of anaphase to most recent data, we summarize the contribution of all proposed mechanisms to chromosome segregation and argue that sliding of interpolar microtubules and depolymerization at the kinetochore are the main drivers of chromosome segregation during early anaphase in human cells.
Highlights
Anaphase as part of the M-phase is one of the most spectacular moments of the cell cycle, when coordinated splitting of replicated chromosomes and segregation of sister chromatids occurs
Confirming the predominance of the plus-end force generation, it was recently shown that a reduction of the number of MTs that end at kinetochores diminishes some of the forces acting on them and that these forces are important for anaphase A movement (Dudka et al, 2018): a reduction of MT occupancy at kinetochores by 30% led to a reduction of anaphase A movement by 40%, without affecting spindle elongation (Dudka et al, 2018)
Powering versus braking chromosome segregation In principle, interpolar MTs can contribute to anaphase dynamics in different ways: in the first scenario, antiparallel MTs slide apart powered by motor proteins that walk towards their plus-end (Fig. 2B,C)
Summary
Anaphase as part of the M-phase is one of the most spectacular moments of the cell cycle, when coordinated splitting of replicated chromosomes and segregation of sister chromatids occurs. Powering versus braking chromosome segregation In principle, interpolar MTs can contribute to anaphase dynamics in different ways: in the first scenario, antiparallel MTs slide apart powered by motor proteins that walk towards their plus-end (Fig. 2B,C) As they slide, the interpolar MTs could push apart different parts of the spindle attached at or near their minus-ends, such as spindle poles (Brust-Mascher et al, 2004), neighboring k-fibers (Vukušić et al, 2017) or the chromosomes (Dumont et al, 2010) (Fig. 2C). We found bridging fibers to be essential for the separation of displaced kinetochores, and continuous cutting of most interpolar MTs in the central spindle decreased spindle elongation rates (Vukušić et al, 2017) In agreement with the latter result, a single-hit laser ablation of all interpolar MTs in human cells immediately stopped anaphase chromosome motion for a short period of time (Yu et al, 2019). These astral MTs can be long enough to interact with proteins at the cell cortex, the actin layer
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