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Genetic modulation of RNA splicing rescues BRCA2 function in mutant cells

2024Journal article Open access
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dc.contributor.authorLima, Beatriz Anjo
dc.contributor.authorPais, Ana Carolina
dc.contributor.authorDupont, Juliette
dc.contributor.authorDias, Patrícia
dc.contributor.authorCustódio, Noélia
dc.contributor.authorSousa, Ana Berta
dc.contributor.authorCarmo-Fonseca, Maria
dc.contributor.authorCarvalho, Célia
dc.date.accessioned2025-02-11T15:01:59Z
dc.date.available2025-02-11T15:01:59Z
dc.date.issued2024
dc.description© 2024 Lima et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).pt_PT
dc.description.abstractVariants in the hereditary cancer-associated BRCA1 and BRCA2 genes can alter RNA splicing, producing transcripts that encode internally truncated yet potentially functional proteins. However, few studies have quantitatively analyzed variant-specific splicing isoforms. Here, we investigated cells heterozygous and homozygous for the BRCA2:c.681+5G>C variant. Using droplet digital RT-PCR, we identified two variant-specific mRNA isoforms. The predominant transcript is out-of-frame, contains a premature termination codon, and is degraded via the nonsense-mediated mRNA decay pathway. In addition, we detected a novel minor isoform encoding an internally truncated protein lacking non-essential domains. Homozygous mutant cells expressed low levels of BRCA2 protein and were defective in DNA repair. Using CRISPR-Cas9 gene editing, we induced the production of in-frame transcripts in mutant cells, which resulted in increased protein expression, enhanced RAD51 focus formation, and reduced chromosomal breaks after exposure to genotoxic agents. Our findings highlight the therapeutic potential of splicing modulation to restore BRCA2 function in mutant cells, offering a promising strategy to prevent cancer development.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal (PTDC/MED-ONC/3921/2021).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationLife Sci Alliance. 2024 Dec 31;8(3):e202402845pt_PT
dc.identifier.doi10.26508/lsa.202402845pt_PT
dc.identifier.eissn2575-1077
dc.identifier.urihttp://hdl.handle.net/10400.5/98330
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherEMBO Presspt_PT
dc.relationImpact of the Portuguese BRCA2 founder mutation on transcription and tissue stem cell identity
dc.relation.publisherversionhttps://www.life-science-alliance.org/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleGenetic modulation of RNA splicing rescues BRCA2 function in mutant cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleImpact of the Portuguese BRCA2 founder mutation on transcription and tissue stem cell identity
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Concurso de Projetos IC&DT em Todos os Domínios Científicos/PTDC%2FMED-ONC%2F3921%2F2021/PT
oaire.citation.issue3pt_PT
oaire.citation.titleLife Science Alliancept_PT
oaire.citation.volume8pt_PT
oaire.fundingStreamConcurso de Projetos IC&DT em Todos os Domínios Científicos
person.familyNameDupont
person.familyNameFernandes Custódio
person.familyNameFonseca Vieira Álvares Sousa Ferrand Almeida
person.familyNameCarmo-Fonseca
person.familyNameCarvalho
person.givenNameJuliette
person.givenNameNoélia Maria
person.givenNameAna Berta
person.givenNameMaria
person.givenNameCélia
person.identifier.ciencia-id441F-D9B0-5E4D
person.identifier.ciencia-id8615-44B3-7645
person.identifier.ciencia-id031D-CFAD-116A
person.identifier.ciencia-idB31F-0435-0753
person.identifier.ciencia-idDD18-667D-59FE
person.identifier.orcid0000-0001-8257-5067
person.identifier.orcid0000-0001-9230-9870
person.identifier.orcid0000-0001-5889-2492
person.identifier.orcid0000-0002-3402-7143
person.identifier.orcid0000-0002-5980-595X
person.identifier.scopus-author-id6508187568
person.identifier.scopus-author-id7007128195
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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