BAP1 Loss In Mesothelioma Induces Genome Instability Through BRCA1-Dependent And Independent Mechanisms

BRCA1 associated protein 1 (BAP1) is a tumour suppressor that is commonly inactivated in a plethora of hereditary and sporadic human malignancies including malignant pleural mesothelioma. However, the biological function and impact of BAP1 disruption in cancer remains poorly defined. The goal of this thesis is to characterize the function of BAP1 in regulating BRCA1 protein stability and reveal the consequence of its loss in mitosis in mesothelioma cells. First, we reveal that BRCA1 regulates spindle assembly checkpoint proteins and controls mitotic progression in response to vinorelbine in mesothelioma cells. Second, we report that BAP1 controls BRCA1 stability in mesothelioma cells with depletion of BAP1 protein inducing proteasomemediated degradation of BRCA1. Hence, BAP1 loss phenocopied the loss of BRCA1 not only in promoting spindle assembly checkpoint failure but also causing centrosome amplification and chromosome segregation errors. However, loss of BAP1 led to additional mitotic defects that were not observed upon BRCA1 loss, including an increase in spindle length and enhanced astral microtubules. Intriguingly, these consequences were explained by loss of expression of the KIF18A and KIF18B kinesin motors in response to BAP1 depletion. Finally, we showed a significant correlation in expression of BAP1 and BRCA1 in tumour samples taken from mesothelioma patients. Hence, we demonstrate both BRCA1-dependent and –independent roles for BAP1 in mitotic progression. Our findings also suggest that BAP1 may predict response to therapeutic agents such as vinorelbine and may be used as a novel biomarker for stratified treatment in mesothelioma.