Dual function of SDS22 in the biogenesis of protein phosphatase-1 holoenzymes

Malignant mesothelioma is an aggressive cancer of the pleura and peritoneal cavities with limited treatment options. We have recently discovered that the pulse phosphorylation of protein kinase BUB1 functions as a timer for mitotic duration. In addition, this ‘BUB1 timer’ sensitizes cancer cells to anti-mitotic drugs and key components of the timer coordinate the (post)mitotic response to DNA-damage. Our objective is to explore whether the prolongation of the BUB1 timer can be used to sensitize mesotheliomas to prevailing combinations of DNA-damaging and anti-mitotic therapies. For this purpose, we will first compare the properties of the BUB1 timer in engineered mesothelial and mesothelioma cell lines. We will proceed to explore BUB1-timer prolonging strategies using temperature-based protocols or small-molecule inhibitors of timer silencing identified through screening of small-molecule libraries. The therapeutic efficacy of timer-prolonging strategies will be tested in cell and mouse models of mesothelioma.