Malignant Pleural Mesothelioma Mutations in Reveal Synthetic Lethality between / and the Proteasome Subunit /.

The deubiquitinase BAP1 (BRCA1-associated protein 1) is associated with tumor predisposition syndrome (TPDS). is a tumor suppressor gene whose alterations in cancer are commonly caused by gene mutations leading to protein loss of function. By CRISPR-Cas, we have generated mutations in , the ortholog in , to model the functional impact of mutations. We have found that a mimicked cancer missense mutation (UBH-4 A87D; BAP1 A95D) resembles the phenotypes of deletion mutants. Despite being ubiquitously expressed, the gene is not essential for viability and its deletion causes only mild phenotypes without affecting 20S proteasome levels. Such viability facilitated an RNAi screen for genetic interactors that identified , the ortholog of human PSMD13, a gene encoding subunit of the regulatory particle of the 26S proteasome. [A87D], similarly to deletion, cause a synthetic genetic interaction with inactivation affecting body size, lifespan, and the development of germ cells. Finally, we show how inactivation sensitizes animals to the chemotherapeutic agent Bortezomib, which is a proteasome inhibitor. Thus, we have established a model to study cancer-related mutations in , and our data points toward vulnerabilities that should be studied to explore therapeutic opportunities within the complexity of tumors.