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BAP1 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 ubh-4, the BAP1 ortholog in Caenorhabditis elegans, to model the functional impact of BAP1 mutations. We have found that a mimicked BAP1 cancer missense mutation (UBH-4 A87D; BAP1 A95D) resembles the phenotypes of ubh-4 deletion mutants. Despite ubh-4 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 ubh-4 genetic interactors that identified rpn-9, the ortholog of human PSMD13, a gene encoding subunit of the regulatory particle of the 26S proteasome. ubh-4[A87D], similarly to ubh-4 deletion, cause a synthetic genetic interaction with rpn-9 inactivation affecting body size, lifespan, and the development of germ cells. Finally, we show how ubh-4 inactivation sensitizes animals to the chemotherapeutic agent Bortezomib, which is a proteasome inhibitor. Thus, we have established a model to study BAP1 cancer-related mutations in C. elegans, and our data points toward vulnerabilities that should be studied to explore therapeutic opportunities within the complexity of BAP1 tumors.<\/jats:p>","DOI":"10.3390\/cells12060929","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T06:48:35Z","timestamp":1679294915000},"page":"929","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4\/BAP1 and the Proteasome Subunit rpn-9\/PSMD13"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1544-4387","authenticated-orcid":false,"given":"Carmen","family":"Mart\u00ednez-Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Modeling Human Diseases in <i>C. elegans<\/i> Group, Genes, Diseases, and Therapies Program, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), L\u2019Hospitalet de Llobregat, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sweta","family":"Jha","sequence":"additional","affiliation":[{"name":"Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabet","family":"Aliagas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Institut Catal\u00e0 d\u2019Oncologia (ICO), L\u2019Hospitalet de Llobregat, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9645-2009","authenticated-orcid":false,"given":"Carina I.","family":"Holmberg","sequence":"additional","affiliation":[{"name":"Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9674-5554","authenticated-orcid":false,"given":"Ernest","family":"Nadal","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Institut Catal\u00e0 d\u2019Oncologia (ICO), L\u2019Hospitalet de Llobregat, 08908 Barcelona, Spain"},{"name":"Preclinical and Experimental Research in Thoracic Tumors (PReTT), Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), L\u2019Hospitalet de Llobregat, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juli\u00e1n","family":"Cer\u00f3n","sequence":"additional","affiliation":[{"name":"Modeling Human Diseases in <i>C. elegans<\/i> Group, Genes, Diseases, and Therapies Program, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge (IDIBELL), L\u2019Hospitalet de Llobregat, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6953","DOI":"10.1158\/0008-5472.CAN-08-0365","article-title":"BAP1 Is a Tumor Suppressor That Requires Deubiquitinating Activity and Nuclear Localization","volume":"68","author":"Ventii","year":"2008","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1093\/jnci\/djy171","article-title":"Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide","volume":"110","author":"Walpole","year":"2018","journal-title":"J. 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