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A Comparative Overview of the Role of Human Ribonucleases in Nonsense-Mediated mRNA Decay

2024-10-10Journal article Open access
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datacite.subject.fosCiências Naturais::Ciências Biológicas
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorda Costa, Paulo J.
dc.contributor.authorMenezes, Juliane
dc.contributor.authorGuedes, Raquel
dc.contributor.authorReis, Filipa P.
dc.contributor.authorTeixeira, Alexandre
dc.contributor.authorSaramago, Margarida
dc.contributor.authorViegas, Sandra C.
dc.contributor.authorArraiano, Cecília M.
dc.contributor.authorRomão, Luísa
dc.date.accessioned2025-01-23T10:44:07Z
dc.date.available2025-01-23T10:44:07Z
dc.date.issued2024-10-10
dc.description(This article belongs to the Special Issue Post-transcriptional Regulation in Mammals)en
dc.description.abstractEukaryotic cells possess surveillance mechanisms that detect and degrade defective transcripts. Aberrant transcripts include mRNAs with a premature termination codon (PTC), targeted by the nonsense-mediated decay (NMD) pathway, and mRNAs lacking a termination codon, targeted by the nonstop decay (NSD) pathway. The eukaryotic exosome, a ribonucleolytic complex, plays a crucial role in mRNA processing and turnover through its catalytic subunits PM/Scl100 (Rrp6 in yeast), DIS3 (Rrp44 in yeast), and DIS3L1. Additionally, eukaryotic cells have other ribonucleases, such as SMG6 and XRN1, that participate in RNA surveillance. However, the specific pathways through which ribonucleases recognize and degrade mRNAs remain elusive. In this study, we characterized the involvement of human ribonucleases, both nuclear and cytoplasmic, in the mRNA surveillance mechanisms of NMD and NSD. We performed knockdowns of SMG6, PM/Scl100, XRN1, DIS3, and DIS3L1, analyzing the resulting changes in mRNA levels of selected natural NMD targets by RT-qPCR. Additionally, we examined the levels of different human β-globin variants under the same conditions: wild-type, NMD-resistant, NMD-sensitive, and NSD-sensitive. Our results demonstrate that all the studied ribonucleases are involved in the decay of certain endogenous NMD targets. Furthermore, we observed that the ribonucleases SMG6 and DIS3 contribute to the degradation of all β-globin variants, with an exception for βNS in the former case. This is also the case for PM/Scl100, which affects all β-globin variants except the NMD-sensitive variants. In contrast, DIS3L1 and XRN1 show specificity for β-globin WT and NMD-resistant variants. These findings suggest that eukaryotic ribonucleases are target-specific rather than pathway-specific. In addition, our data suggest that ribonucleases play broader roles in mRNA surveillance and degradation mechanisms beyond just NMD and NSD.eng
dc.description.sponsorshipFunding: This work was partially supported by Instituto Nacional de Saúde Doutor Ricardo Jorge and Fundação para a Ciência e a Tecnologia (FCT), Portugal [UIDB/04046/2020 (DOI: 10.54499/UIDB/ 04046/2020), and UIDP/04046/2020 (https://doi.org/10.54499/UIDP/04046/2020) Centre grants from FCT (to BioISI)]. P.J.d.C. was recipient of a fellowship from the BioSys PhD programme (SFRH/BD/52495/2014) and J.M. was a postdoc fellow (SFRH/BPD/98360/2013) from FCT. Work at ITQB-NOVA was financially supported by FCT, Project MOSTMICRO-ITQB with references UIDB/04612/2020 and UIDP/04612/2020, and LS4FUTURE Associated Laboratory (LA/P/0087/ 2020). M.S. is a recipient of FCT DL57.
dc.identifier.citationGenes (Basel). 2024 Oct 10;15(10):1308. doi: 10.3390/genes15101308
dc.identifier.doihttps://doi.org/10.3390/genes15101308
dc.identifier.eissn2073-4425
dc.identifier.pmid39457432
dc.identifier.urihttp://hdl.handle.net/10400.18/10317
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI
dc.relationBiosystems and Integrative Sciences Institute
dc.relationUIDB/04612/2020
dc.relationUIDB/04046/2020
dc.relationUIDP/04046/2020
dc.relationSFRH/BD/52495/2014
dc.relationSFRH/BPD/98360/2013
dc.relationUIDP/04612/2020
dc.relation.hasversionhttps://www.mdpi.com/2073-4425/15/10/1308
dc.rights.uriN/A
dc.subjectmRNA Surveillance
dc.subjectQuality Control
dc.subjectNonsense-mediated mRNA Decay (NMD)
dc.subjectNonstop Decay
dc.subjectmRNA Degradation
dc.subjectNatural NMD Targets
dc.subjectGenómica Funcional e Estrutural
dc.titleA Comparative Overview of the Role of Human Ribonucleases in Nonsense-Mediated mRNA Decayeng
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04046%2F2020/PT
oaire.citation.issue10
oaire.citation.startPage1308
oaire.citation.titleGenes (Basel)
oaire.citation.volume15
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
relation.isProjectOfPublicationdc433369-36fd-4935-bd52-c56aa49c72e1
relation.isProjectOfPublication.latestForDiscoverydc433369-36fd-4935-bd52-c56aa49c72e1

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