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mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion

mRNAs containing premature termination codons (PTCs) are rapidly degraded through nonsense-mediated mRNA decay (NMD). However, some PTC-containing mRNAs evade NMD, and might generate mutant proteins responsible for various diseases, including cancers. Using PTC-containing human genomic β-globin cons...

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Autores principales: Kim, Won Kyu, Yun, SeongJu, Kwon, Yujin, You, Kwon Tae, Shin, Nara, Kim, Jiyoon, Kim, Hoguen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696521/
https://www.ncbi.nlm.nih.gov/pubmed/29158530
http://dx.doi.org/10.1038/s41598-017-16177-9
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author Kim, Won Kyu
Yun, SeongJu
Kwon, Yujin
You, Kwon Tae
Shin, Nara
Kim, Jiyoon
Kim, Hoguen
author_facet Kim, Won Kyu
Yun, SeongJu
Kwon, Yujin
You, Kwon Tae
Shin, Nara
Kim, Jiyoon
Kim, Hoguen
author_sort Kim, Won Kyu
collection PubMed
description mRNAs containing premature termination codons (PTCs) are rapidly degraded through nonsense-mediated mRNA decay (NMD). However, some PTC-containing mRNAs evade NMD, and might generate mutant proteins responsible for various diseases, including cancers. Using PTC-containing human genomic β-globin constructs, we show that a fraction (~30%) of PTC-containing mRNAs expressed from NMD-competent PTC-containing constructs were as stable as their PTC-free counterparts in a steady state. These PTC-containing mRNAs were monosome-enriched and rarely contributed to expression of mutant proteins. Expression of trace amounts of mutant proteins from NMD-competent PTC-containing constructs was not affected by inhibition of eIF4E-dependent translation and such expression was dependent on a continuous influx of newly synthesized PTC-containing mRNAs, indicating that truncated mutant proteins originated primarily in the pioneer round of translation. The generation of mutant proteins was promoted by UPF1 depletion, which induced polysome association of PTC-containing mRNAs, increased eIF4E-bound PTC-containing mRNA levels, and subsequent eIF4E-dependent translation. Our findings suggest that PTC-containing mRNAs are potent and regulatable sources of mutant protein generation.
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spelling pubmed-56965212017-11-29 mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion Kim, Won Kyu Yun, SeongJu Kwon, Yujin You, Kwon Tae Shin, Nara Kim, Jiyoon Kim, Hoguen Sci Rep Article mRNAs containing premature termination codons (PTCs) are rapidly degraded through nonsense-mediated mRNA decay (NMD). However, some PTC-containing mRNAs evade NMD, and might generate mutant proteins responsible for various diseases, including cancers. Using PTC-containing human genomic β-globin constructs, we show that a fraction (~30%) of PTC-containing mRNAs expressed from NMD-competent PTC-containing constructs were as stable as their PTC-free counterparts in a steady state. These PTC-containing mRNAs were monosome-enriched and rarely contributed to expression of mutant proteins. Expression of trace amounts of mutant proteins from NMD-competent PTC-containing constructs was not affected by inhibition of eIF4E-dependent translation and such expression was dependent on a continuous influx of newly synthesized PTC-containing mRNAs, indicating that truncated mutant proteins originated primarily in the pioneer round of translation. The generation of mutant proteins was promoted by UPF1 depletion, which induced polysome association of PTC-containing mRNAs, increased eIF4E-bound PTC-containing mRNA levels, and subsequent eIF4E-dependent translation. Our findings suggest that PTC-containing mRNAs are potent and regulatable sources of mutant protein generation. Nature Publishing Group UK 2017-11-20 /pmc/articles/PMC5696521/ /pubmed/29158530 http://dx.doi.org/10.1038/s41598-017-16177-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kim, Won Kyu
Yun, SeongJu
Kwon, Yujin
You, Kwon Tae
Shin, Nara
Kim, Jiyoon
Kim, Hoguen
mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion
title mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion
title_full mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion
title_fullStr mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion
title_full_unstemmed mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion
title_short mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion
title_sort mrnas containing nmd-competent premature termination codons are stabilized and translated under upf1 depletion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696521/
https://www.ncbi.nlm.nih.gov/pubmed/29158530
http://dx.doi.org/10.1038/s41598-017-16177-9
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