BAP1 is a ubiquitin C-terminal hydrolase (UCH) that presents a powerful tumor suppressor activity. There are many studies associating BAP1 mutations to certain types of cancer, grouped in the BAP1 tumor predisposition syndrome (BAP1-TPDS). However, the functional consequences of BAP1 cancer-related alterations are still largely unknown. We aimed to establish a model to investigate the impact of BAP1-TPDS-related mutations using C. elegans and CRISPR-Cas9. First, we generated distinct
ubh-4 strains: two harboring missense mutations found in malignant pleural mesothelioma patients (A87D and F73V) and two with deletion alleles. None of these mutations affect animal viability. Next, to identify
ubh-4 genetic interactors, we performed an RNAi screen on an
ubh-4 null background with more than a hundred genes related to the ubiquitin proteasome system (UPS) and cancer. We uncovered a strong synthetic genetic interaction between
ubh-4 and
rpn-9, an essential regulatory subunit of the 19S proteasome involved in proteasome assembly. Further validation of RNAi results with mutations revealed a detrimental effect of the null allele and the A87D cancer-related mutation on animal size, lifespan, and germline development only combined with
rpn-9 mutant background. In line with these observations, we noted that UBH-4:EGFP and RPN-9:wrmScarlet endogenous reporter, generated by Nested CRISPR, showed high expression and co-expression at meiotic regions, suggesting that
ubh-4 and
rpn-9 cooperate in meiotic progression by modulating ubiquitin-mediated proteostasis. Finally, we have preliminary results indicating that the
ubh-4 null mutant is sensitive to the proteasome inhibitor Bortezomib. Thus, our data suggest that pharmacological targeting of PSMD13/RPN-9 or the 19S regulatory complex could be utilized to compromise cell viability in BAP1-mutated tumors.