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Harry, Edward
Languages: English
Types: Doctoral thesis
Subjects: QH
Kinetochores are multi-protein machines that control chromosome movements by regulating the dynamics of attached microtubules. In human cells chromosome movements are orchestrated by the leading kinetochore tracking a shrinking microtubule whilst its sister tracks a growing microtubule. Directional switches occur when (both) kinetochore-attached microtubules fl\ud ip between these two states, adaptive and coordinated switching then giving rise to the oscillations observed during metaphase. However the mechanisms (and rules) controlling directional switching are poorly understood. This work demonstrates that by tracking kinetochores with sub-pixel resolution in HeLa cells and fitting stochastic mathematical models that a sensor on the leading sister triggers switching when the tension across the centromeric spring connecting the sisters builds up sufficiently rapidly. Further it is shown that the trailing sisters polymerisation state is stabilised by high spring tension. These mechanisms pre-empt trail-first switching that would otherwise impose abnormal pulling forces between sister chromatids. As a consequence sister-switching is biased towards lead-first switching, switching of the trailing sister rapidly following as the spring tension falls, this removing the force dependent stabilisation of the trailing sisters K-fibre (kinetochore bound microtubules). This model explains how switching events are initiated and resolved, the centromeric spring tension providing a means for inter-sister communication and cross regulation that results in coordinated oscillations within a context of low spring tension. This study demonstrates that high throughput analysis and modelling pipelines can provide novel mechanistic insight into mechanochemical systems.
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