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http://hdl.handle.net/2445/198334
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DC Field | Value | Language |
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dc.contributor.author | Martínez Fernández, Carmen | - |
dc.contributor.author | Jha, Sweta | - |
dc.contributor.author | Aliagas, Elisabet | - |
dc.contributor.author | Holmberg, Carina I. | - |
dc.contributor.author | Nadal, Ernest | - |
dc.contributor.author | Cerón, Julián | - |
dc.date.accessioned | 2023-05-23T11:15:39Z | - |
dc.date.available | 2023-05-23T11:15:39Z | - |
dc.date.issued | 2023-03-18 | - |
dc.identifier.issn | 2073-4409 | - |
dc.identifier.uri | http://hdl.handle.net/2445/198334 | - |
dc.description.abstract | The deubiquitinase BAP1 (BRCA1-associated protein 1) is associated with BAP1 tumor predisposition syndrome (TPDS). 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. | - |
dc.format.extent | 17 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | MDPI AG | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.3390/cells12060929 | - |
dc.relation.ispartof | Cells, 2023, vol. 12, num. 6, p. 929 | - |
dc.relation.uri | https://doi.org/10.3390/cells12060929 | - |
dc.rights | cc by (c) Martínez Fernández, Carmen et al., 2023 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) | - |
dc.subject.classification | Mesotelioma | - |
dc.subject.classification | Nematodes | - |
dc.subject.classification | Quimioteràpia | - |
dc.subject.other | Mesothelioma | - |
dc.subject.other | Nematodes | - |
dc.subject.other | Chemotherapy | - |
dc.title | BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13 | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2023-04-17T13:45:53Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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cells-12-00929.pdf | 7.55 MB | Adobe PDF | View/Open |
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