A mechanobiochemical mechanism for monooriented chromosome oscillation in mitosis

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Abstract
During mitosis, the condensed chromosomes undergo a series of spectacular oscillations after they are captured in an end-on manner by kinetochore microtubules (KMT) emanating from the spindle poles. Such oscillations are commonly attributed to tug-of-war-like mechanisms, where the mechanical force imbalance alone drives the chromosome movement. However, a large portion of the force imbalance upon the chromosome is absorbed by the kinetochore and may not drive chromosome movement directly. Mounting evidence suggests that such resistance by the kinetochores regulates the chemical reactions of KMT plus-end growth and shrinkage, which have been shown as the determinant of the chromosome antipoleward (AP) and poleward movements. Here we incorporate this important regulatory feature, propose a mechanobiochemical feedback mechanism, and apply it to the monooriented chromosome oscillation, the early stage of the series of observed chromosome oscillations. In this model, the mechanical movement of the chromosome and the local biochemical reactions at the attached kinetochore region form a feedback loop that drives the oscillation. The force imbalance exerted on the chromosomes provides a bias (via mechanically sensitive proteins) on the local biochemical reactions controlling the KMT plus-end dynamics, and the movement of the chromosome in turn changes the forces exerted on it through the experimentally supported gradient in AP force. The proposed feedback mechanism can generate oscillatory behavior that depends on the topology of the feedback loop but is largely independent of the detailed molecular mechanism. We suggest potential molecular players, whose perturbation may allow direct experimental tests of the model.