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Molecular timers of the spindle assembly checkpoint

The spindle assembly checkpoint (SAC) is a cellular surveillance mechanism that delays the separation of duplicated chromosomes until their proper connection to the microtubule-based machinery that pulls them apart. We have recently discovered a molecular timing mechanism that entails the transient binding of a phosphate group to the SAC protein BUB1. This ‘BUB1 timer’ sets the minimum time to establish mature chromosome-microtubule interactions during mitosis and makes the SAC more responsive to attachment problems. Preventing BUB1-timer silencing holds great potential for cancer therapy. Here, we propose to compare the properties of the BUB1 timer in normal cells and cancer cells with engineered timer durations. These cell lines will also be instrumental to delineate the contribution of the BUB1 timer to the coordination of SAC signaling and the response to DNA damage. Another point of attention relates to the mechanism by which the BUB1 timer sensitizes the SAC to microtubule poisons. Finally, we aim to develop BUB1-timer prolonging strategies using temperature-based protocols and/or small-molecule inhibitors of timer silencing identified through screening of small-molecule libraries. Validated inhibitors of timer silencing will be tested for their ability to kill cancer cells and sensitize them to cytotoxic drugs. This fundamental research project aims to obtain key insights into the properties of the BUB1 timer and the therapeutic potential of prolonging this time

Date:1 Jan 2019  →  Today
Keywords:Medical sciences, Biologic sciences
Disciplines:Cell signalling