Summary

Kinetochores are adaptive, multi-layered mechanochemical machines that assemble at the centromere of each sister chromatid and engage on their outer face with the plus ends of k-fibres, microtubule bundles that emanate from the spindle poles. We envision the kinetochore as a set of interacting springs, clutches and motors and the problem of kinetochore mechanism as one of understanding how these functional modules assemble, disassemble and interact with one another to give rise the emergent properties of the kinetochore. Incisive experiments made over 17 years ago revealed that once sister kinetochores become attached to microtubules emanating from opposite poles (biorientation), they undergo a series of oscillations - termed chromosome directional instability - prior to anaphase onset. However, neither the mechanisms nor purpose of kinetochore directional switching in human cells is well understood. We propose a parallel approach employing mathematical modeling in tandem with higher-resolution tracking experiments of both native kinetochores and kinetochores specifically depleted of specific protein components. Oscillation is a high-level emergent property, providing a read-out of functional competence and a stringent quantitative test for the accuracy of our model. Iteratively refining the model in the light of our real-world data on oscillations will enumerate and deconvolve the contributions of mechanical components of the kinetochore to its emergent behaviour. We also expect to provide the first insight into the function of chromosome oscillations in animal cells.