BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4 / BAP1 and the Proteasome Subunit rpn-9 / PSMD13

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 6; p. 929
• Main Authors: Martínez-Fernández, Carmen, Jha, Sweta, Aliagas, Elisabet, Holmberg, Carina I, Nadal, Ernest, Cerón, Julián
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18-03-2023; MDPI
• Subjects: Animals; BAP1; Body size; Bortezomib; BRCA1 protein; C. elegans; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Cancer; Cell cycle; Cloning; CRISPR; Deletion mutant; Disease Models, Animal; Gene deletion; Germ cells; Humans; Lethality; Life sciences; Life span; Malignant Pleural Mesothelioma; Mesothelioma; Mesothelioma - genetics; Mesothelioma - pathology; Mesothelioma, Malignant - genetics; Missense mutation; Mutation; Mutation - genetics; Nematodes; Phenotypes; Proteasome 26S; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteasomes; Proteins; PSMD13; RNA-mediated interference; rpn-9; Statistical analysis; Synthetic Lethal Mutations; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumors; ubh-4; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Worms; United States > US; Germany; proteasome; C. elegans; Bortezomib; PSMD13; rpn-9; CRISPR-Cas; Malignant Pleural Mesothelioma; ubh-4; BAP1
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12060929

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.