Towards a quantitative comprehension of the Spindle Assembly Checkpoint (360G-Wellcome-209470_Z_17_Z)

My aim is to complete a quantitative analysis of the dynamic signalling pathways that control mitosis. By combining mass spectrometry with cutting-edge microsopy I intend to measure the number of active molecules of the key mitotic regulators and determine how and where they interact to generate a highly responsive signal transduction network that ensures genomic stability by controlling sister chromatid separation and mitotic exit. I have four main aims: 1) Measure the numbers of the mitotic regulators controlling chromosome separation and analyse how they are modulated by post-translational modifications (PTMs). 2) Determine the dynamics of the spindle assembly checkpoint (SAC) in living cells by measuring the generation of the SAC effector complex and the flux of its components through the pathway. 3) Determine how changes to a kinetochore affect its ability to catalyse the generation of the MCC. 4) Determine how a defined change in the number of molecules of specific regulators alters the dynamics and strength of the SAC, and in consequence their effect on genomic stability. Together, these studies will be used to inform and discriminate between models of mitotic control to determine how the SAC combines the properties of potency and responsiveness.