| Summary: | The deubiquitinase BAP1 (BRCA1-associated protein 1) is associated with <i>BAP1</i> tumor predisposition syndrome (TPDS). <i>BAP1</i> 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 <i>ubh-4</i>, the <i>BAP1</i> ortholog in <i>Caenorhabditis elegans</i>, to model the functional impact of <i>BAP1</i> mutations. We have found that a mimicked <i>BAP1</i> cancer missense mutation (UBH-4 A87D; BAP1 A95D) resembles the phenotypes of <i>ubh-4</i> deletion mutants. Despite <i>ubh-4</i> 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 <i>ubh-4</i> genetic interactors that identified <i>rpn-9</i>, the ortholog of human PSMD13, a gene encoding subunit of the regulatory particle of the 26S proteasome. <i>ubh-4</i>[A87D], similarly to <i>ubh-4</i> deletion, cause a synthetic genetic interaction with <i>rpn-9</i> inactivation affecting body size, lifespan, and the development of germ cells. Finally, we show how <i>ubh-4</i> inactivation sensitizes animals to the chemotherapeutic agent Bortezomib, which is a proteasome inhibitor. Thus, we have established a model to study <i>BAP1</i> cancer-related mutations in <i>C. elegans</i>, and our data points toward vulnerabilities that should be studied to explore therapeutic opportunities within the complexity of <i>BAP1</i> tumors.
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