Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling

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dc.citation.articleNumbere2405231121en_US
dc.citation.issueNumber29en_US
dc.citation.journalTitleProceedings of the National Academy of Sciencesen_US
dc.citation.volumeNumber121en_US
dc.contributor.authorNovelli, Flaviaen_US
dc.contributor.authorYoshikawa, Yoshieen_US
dc.contributor.authorVitto, Veronica Angela Mariaen_US
dc.contributor.authorModesti, Lorenzoen_US
dc.contributor.authorMinaai, Michaelen_US
dc.contributor.authorPastorino, Sandraen_US
dc.contributor.authorEmi, Mitsuruen_US
dc.contributor.authorKim, Jin-Heeen_US
dc.contributor.authorKricek, Franzen_US
dc.contributor.authorBai, Fangen_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.authorBononi, Angelaen_US
dc.contributor.authorSuarez, Joelle S.en_US
dc.contributor.authorTanji, Mikaen_US
dc.contributor.authorFavaron, Cristinaen_US
dc.contributor.authorZolondick, Alicia A.en_US
dc.contributor.authorXu, Ronghuien_US
dc.contributor.authorTakanishi, Yasutakaen_US
dc.contributor.authorWang, Zhanweien_US
dc.contributor.authorSakamoto, Gregen_US
dc.contributor.authorGaudino, Giovannien_US
dc.contributor.authorGrzymski, Josephen_US
dc.contributor.authorGrosso, Federicaen_US
dc.contributor.authorSchrump, David S.en_US
dc.contributor.authorPass, Harvey I.en_US
dc.contributor.authorAtanesyan, Liliten_US
dc.contributor.authorSmout, Janen_US
dc.contributor.authorSavola, Suvien_US
dc.contributor.authorSarin, Kavita Y.en_US
dc.contributor.authorAbolhassani, Hassanen_US
dc.contributor.authorHammarström, Lennarten_US
dc.contributor.authorPan-Hammarström, Qiangen_US
dc.contributor.authorGiorgi, Carlottaen_US
dc.contributor.authorPinton, Paoloen_US
dc.contributor.authorYang, Hainingen_US
dc.contributor.authorCarbone, Micheleen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2024-08-09T16:25:26Zen_US
dc.date.available2024-08-09T16:25:26Zen_US
dc.date.issued2024en_US
dc.description.abstractWe report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.en_US
dc.identifier.citationNovelli, F., Yoshikawa, Y., Vitto, V. A. M., Modesti, L., Minaai, M., Pastorino, S., Emi, M., Kim, J.-H., Kricek, F., Bai, F., Onuchic, J. N., Bononi, A., Suarez, J. S., Tanji, M., Favaron, C., Zolondick, A. A., Xu, R., Takanishi, Y., Wang, Z., … Carbone, M. (2024). Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling. Proceedings of the National Academy of Sciences, 121(29), e2405231121. https://doi.org/10.1073/pnas.2405231121en_US
dc.identifier.digitalnovelli-et-al-2024en_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2405231121en_US
dc.identifier.urihttps://hdl.handle.net/1911/117638en_US
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleGermline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signalingen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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