The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames

Detalhes bibliográficos
Autor(a) principal: Onofre, Cláudia
Data de Publicação: 2016
Outros Autores: Menezes, Juliane, Peixeiro, Isabel, Barbosa, Cristina, Romão, Luísa
Tipo de documento: Artigo de conferência
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.18/4508
Resumo: Mammalian nonsense-mediated mRNA decay (NMD) is a splicing- and translation-dependent surveillance pathway that recognizes and selectively degrades mRNAs carrying premature termination codons (PTCs). In addition, several studies have also implicated NMD in the regulation of steady-state levels of physiological mRNAs, and examples of natural NMD targets are transcripts containing upstream short open reading frames or long 3’ untranslated regions. The strength of the NMD response appears to reflect multiple determinants on a target mRNA. In general, the location of a PTC greater than 50 nucleotides upstream to the last exon-exon junction constitutes a major determinant of NMD. However, we have reported that human mRNAs with a PTC in close proximity to the translation initiation codon (AUG-proximal PTC), and thus, with a short open reading frame, can substantially escape NMD. Our data support a model in which cytoplasmic poly(A)-binding protein 1 (PABPC1) is brought into close proximity with an AUG-proximal PTC via interactions with the translation initiation complexes. This proximity of PABPC1 to the AUG-proximal PTC allows PABPC1 to interact with eRF3 with a consequent enhancement of the release reaction and repression of the NMD response. Here, we present strong evidence that the eIF3 is involved in delivering eIF4G-associated PABPC1 into the vicinity of the AUG-proximal PTC. In addition, we dissect the biochemical interactions of the eIF3 subunits in bridging PABPC1/eIF4G complex to the 40S ribosomal subunit. Together, our data provide a framework for understanding the mechanistic details of PTC definition and translation initiation.
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spelling The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading framesGenómica Funcional e EstruturalExpressão GénicaNonsense-mediated mRNA DecayMammalian nonsense-mediated mRNA decay (NMD) is a splicing- and translation-dependent surveillance pathway that recognizes and selectively degrades mRNAs carrying premature termination codons (PTCs). In addition, several studies have also implicated NMD in the regulation of steady-state levels of physiological mRNAs, and examples of natural NMD targets are transcripts containing upstream short open reading frames or long 3’ untranslated regions. The strength of the NMD response appears to reflect multiple determinants on a target mRNA. In general, the location of a PTC greater than 50 nucleotides upstream to the last exon-exon junction constitutes a major determinant of NMD. However, we have reported that human mRNAs with a PTC in close proximity to the translation initiation codon (AUG-proximal PTC), and thus, with a short open reading frame, can substantially escape NMD. Our data support a model in which cytoplasmic poly(A)-binding protein 1 (PABPC1) is brought into close proximity with an AUG-proximal PTC via interactions with the translation initiation complexes. This proximity of PABPC1 to the AUG-proximal PTC allows PABPC1 to interact with eRF3 with a consequent enhancement of the release reaction and repression of the NMD response. Here, we present strong evidence that the eIF3 is involved in delivering eIF4G-associated PABPC1 into the vicinity of the AUG-proximal PTC. In addition, we dissect the biochemical interactions of the eIF3 subunits in bridging PABPC1/eIF4G complex to the 40S ribosomal subunit. Together, our data provide a framework for understanding the mechanistic details of PTC definition and translation initiation.This work was partially supported by Fundação Luso-Americana para o Desenvolvimento and Fundação para a Ciência e a Tecnologia (UID/MULTI/04046/2013 to BioISI from FCT/MCTES/PIDDAC).Repositório Científico do Instituto Nacional de SaúdeOnofre, CláudiaMenezes, JulianePeixeiro, IsabelBarbosa, CristinaRomão, Luísa2016-09-132025-01-01T00:00:00Z2016-09-13T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectapplication/pdfhttp://hdl.handle.net/10400.18/4508enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:40:15Zoai:repositorio.insa.pt:10400.18/4508Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:39:02.613892Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
title The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
spellingShingle The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
Onofre, Cláudia
Genómica Funcional e Estrutural
Expressão Génica
Nonsense-mediated mRNA Decay
title_short The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
title_full The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
title_fullStr The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
title_full_unstemmed The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
title_sort The interplay between mRNA translation and nonsense-mediated decay in transcripts with short open reading frames
author Onofre, Cláudia
author_facet Onofre, Cláudia
Menezes, Juliane
Peixeiro, Isabel
Barbosa, Cristina
Romão, Luísa
author_role author
author2 Menezes, Juliane
Peixeiro, Isabel
Barbosa, Cristina
Romão, Luísa
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Nacional de Saúde
dc.contributor.author.fl_str_mv Onofre, Cláudia
Menezes, Juliane
Peixeiro, Isabel
Barbosa, Cristina
Romão, Luísa
dc.subject.por.fl_str_mv Genómica Funcional e Estrutural
Expressão Génica
Nonsense-mediated mRNA Decay
topic Genómica Funcional e Estrutural
Expressão Génica
Nonsense-mediated mRNA Decay
description Mammalian nonsense-mediated mRNA decay (NMD) is a splicing- and translation-dependent surveillance pathway that recognizes and selectively degrades mRNAs carrying premature termination codons (PTCs). In addition, several studies have also implicated NMD in the regulation of steady-state levels of physiological mRNAs, and examples of natural NMD targets are transcripts containing upstream short open reading frames or long 3’ untranslated regions. The strength of the NMD response appears to reflect multiple determinants on a target mRNA. In general, the location of a PTC greater than 50 nucleotides upstream to the last exon-exon junction constitutes a major determinant of NMD. However, we have reported that human mRNAs with a PTC in close proximity to the translation initiation codon (AUG-proximal PTC), and thus, with a short open reading frame, can substantially escape NMD. Our data support a model in which cytoplasmic poly(A)-binding protein 1 (PABPC1) is brought into close proximity with an AUG-proximal PTC via interactions with the translation initiation complexes. This proximity of PABPC1 to the AUG-proximal PTC allows PABPC1 to interact with eRF3 with a consequent enhancement of the release reaction and repression of the NMD response. Here, we present strong evidence that the eIF3 is involved in delivering eIF4G-associated PABPC1 into the vicinity of the AUG-proximal PTC. In addition, we dissect the biochemical interactions of the eIF3 subunits in bridging PABPC1/eIF4G complex to the 40S ribosomal subunit. Together, our data provide a framework for understanding the mechanistic details of PTC definition and translation initiation.
publishDate 2016
dc.date.none.fl_str_mv 2016-09-13
2016-09-13T00:00:00Z
2025-01-01T00:00:00Z
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