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Nonsense suppression therapies in human genetic diseases

2021-03-22Journal article Restricted access
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dc.contributor.authorMartins-Dias, Patrícia
dc.contributor.authorRomão, Luísa
dc.date.accessioned2022-02-07T16:31:31Z
dc.date.available2022-02-07T16:31:31Z
dc.date.issued2021-03-22
dc.descriptionReviewpt_PT
dc.description.abstractAbout 11% of all human disease-associated gene lesions are nonsense mutations, resulting in the introduction of an in-frame premature translation-termination codon (PTC) into the protein-coding gene sequence. When translated, PTC-containing mRNAs originate truncated and often dysfunctional proteins that might be non-functional or have gain-of-function or dominant-negative effects. Therapeutic strategies aimed at suppressing PTCs to restore deficient protein function—the so-called nonsense suppression (or PTC readthrough) therapies—have the potential to provide a therapeutic benefit for many patients and in a broad range of genetic disorders, including cancer. These therapeutic approaches comprise the use of translational readthrough-inducing compounds that make the translational machinery recode an in-frame PTC into a sense codon. However, most of the mRNAs carrying a PTC can be rapidly degraded by the surveillance mechanism of nonsense-mediated decay (NMD), thus decreasing the levels of PTC-containing mRNAs in the cell and their availability for PTC readthrough. Accordingly, the use of NMD inhibitors, or readthrough-compound potentiators, may enhance the efficiency of PTC suppression. Here, we review the mechanisms of PTC readthrough and their regulation, as well as the recent advances in the development of novel approaches for PTC suppression, and their role in personalized medicine.pt_PT
dc.description.sponsorshipThis work was partially supported by UID/MULTI/04046/2019 Research Unit Grant (to BioISI) and by PTFC/BIM-MEC/3749/2014 research Grant (to LR) from Fundação para a Ciência e a Tecnologia, Portugal.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCell Mol Life Sci. 2021 May;78(10):4677-4701. doi: 10.1007/s00018-021-03809-7. Epub 2021 Mar 22. Reviewpt_PT
dc.identifier.doi10.1007/s00018-021-03809-7pt_PT
dc.identifier.issn1420-682X
dc.identifier.urihttp://hdl.handle.net/10400.18/7942
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer/ Birkhäuser Verlagpt_PT
dc.relationPTFC/BIM-MEC/3749/2014pt_PT
dc.relationBiosystems & Integrative Sciences Institute
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s00018-021-03809-7pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectNonsense Mutationpt_PT
dc.subjectPremature Termination Codon (PTC)pt_PT
dc.subjectReadthrough Therapypt_PT
dc.subjectStop Codon Readthroughpt_PT
dc.subjectTranslation Terminationpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectGenómica Funcionalpt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleNonsense suppression therapies in human genetic diseasespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT
oaire.citation.endPage4701pt_PT
oaire.citation.issue10pt_PT
oaire.citation.startPage4677pt_PT
oaire.citation.titleCellular and Molecular Life Sciencespt_PT
oaire.citation.volume78pt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameRomão
person.givenNameLuísa
person.identifierhttps://scholar.google.pt/citations?hl=pt-PT&user=CAHjIsoAAAAJ&cstart=60&pagesize=20
person.identifier.ciencia-idEB19-DF07-EB37
person.identifier.orcid0000-0002-5061-5287
person.identifier.scopus-author-idhttp://www.scopus.com/authid/detail.url?authorId=6602834878
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscoverye2eb8254-24ed-4bfc-b478-3e9022f729e2
relation.isProjectOfPublication35168786-8dfc-4a00-9759-dab3669fe1ae
relation.isProjectOfPublication.latestForDiscovery35168786-8dfc-4a00-9759-dab3669fe1ae

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