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SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo

Nonsense-mediated mRNA decay (NMD) protects cells from the toxic and potentially dominant effects of truncated proteins. Targeting of mRNAs with early stop codons is mediated by the ribosome and spatiotemporally aligned with translation termination. Previously we identified a novel NMD intermediate:...

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Autores principales: Kim, John H, Modena, Matthew S, Sehgal, Enisha, Courney, Annie, Neudorf, Celine W, Arribere, Joshua A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9410879/
https://www.ncbi.nlm.nih.gov/pubmed/35950494
http://dx.doi.org/10.1093/nar/gkac681
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author Kim, John H
Modena, Matthew S
Sehgal, Enisha
Courney, Annie
Neudorf, Celine W
Arribere, Joshua A
author_facet Kim, John H
Modena, Matthew S
Sehgal, Enisha
Courney, Annie
Neudorf, Celine W
Arribere, Joshua A
author_sort Kim, John H
collection PubMed
description Nonsense-mediated mRNA decay (NMD) protects cells from the toxic and potentially dominant effects of truncated proteins. Targeting of mRNAs with early stop codons is mediated by the ribosome and spatiotemporally aligned with translation termination. Previously we identified a novel NMD intermediate: ribosomes stalled on cleaved stop codons, raising the possibility that NMD begins even prior to ribosome removal from the stop codon. Here we show that this intermediate is the result of mRNA cleavage by the endonuclease SMG-6. Our work supports a model in which ribosomes stall secondary to SMG-6 mRNA cleavage in Caenorhabditis elegans and humans, i.e. that the novel NMD intermediate occurs after a prior ribosome elicits NMD. Our genetic analysis of C. elegans’ SMG-6 supports a central role for SMG-6 in metazoan NMD, and provides a context for evaluating its function in other metazoans.
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spelling pubmed-94108792022-08-26 SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo Kim, John H Modena, Matthew S Sehgal, Enisha Courney, Annie Neudorf, Celine W Arribere, Joshua A Nucleic Acids Res RNA and RNA-protein complexes Nonsense-mediated mRNA decay (NMD) protects cells from the toxic and potentially dominant effects of truncated proteins. Targeting of mRNAs with early stop codons is mediated by the ribosome and spatiotemporally aligned with translation termination. Previously we identified a novel NMD intermediate: ribosomes stalled on cleaved stop codons, raising the possibility that NMD begins even prior to ribosome removal from the stop codon. Here we show that this intermediate is the result of mRNA cleavage by the endonuclease SMG-6. Our work supports a model in which ribosomes stall secondary to SMG-6 mRNA cleavage in Caenorhabditis elegans and humans, i.e. that the novel NMD intermediate occurs after a prior ribosome elicits NMD. Our genetic analysis of C. elegans’ SMG-6 supports a central role for SMG-6 in metazoan NMD, and provides a context for evaluating its function in other metazoans. Oxford University Press 2022-08-11 /pmc/articles/PMC9410879/ /pubmed/35950494 http://dx.doi.org/10.1093/nar/gkac681 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle RNA and RNA-protein complexes
Kim, John H
Modena, Matthew S
Sehgal, Enisha
Courney, Annie
Neudorf, Celine W
Arribere, Joshua A
SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo
title SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo
title_full SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo
title_fullStr SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo
title_full_unstemmed SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo
title_short SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo
title_sort smg-6 mrna cleavage stalls ribosomes near premature stop codons in vivo
topic RNA and RNA-protein complexes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9410879/
https://www.ncbi.nlm.nih.gov/pubmed/35950494
http://dx.doi.org/10.1093/nar/gkac681
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