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Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay
Nonsense-mediated decay (NMD) is a pathway that degrades mRNAs containing premature termination codons. Here we describe a genome-wide screen for NMD factors that uncovers an unexpected mechanism that broadly governs 3′ untranslated region (UTR)-directed regulation. The screen reveals that NMD requi...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433747/ https://www.ncbi.nlm.nih.gov/pubmed/32668236 http://dx.doi.org/10.1016/j.celrep.2020.107895 |
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author | Zhu, Xiaoqiang Zhang, He Mendell, Joshua T. |
author_facet | Zhu, Xiaoqiang Zhang, He Mendell, Joshua T. |
author_sort | Zhu, Xiaoqiang |
collection | PubMed |
description | Nonsense-mediated decay (NMD) is a pathway that degrades mRNAs containing premature termination codons. Here we describe a genome-wide screen for NMD factors that uncovers an unexpected mechanism that broadly governs 3′ untranslated region (UTR)-directed regulation. The screen reveals that NMD requires lysosomal acidification, which allows transferrin-mediated iron uptake, which, in turn, is necessary for iron-sulfur (Fe-S) cluster biogenesis. This pathway maintains the activity of the Fe-S cluster-containing ribosome recycling factor ABCE1, whose impaired function results in movement of ribosomes into 3′ UTRs, where they displace exon junction complexes, abrogating NMD. Importantly, these effects extend beyond NMD substrates, with ABCE1 activity required to maintain the accessibility of 3′ UTRs to diverse regulators, including microRNAs and RNA binding proteins. Because of the sensitivity of the Fe-S cluster of ABCE1 to iron availability and reactive oxygen species, these findings reveal an unanticipated vulnerability of 3′ UTR-directed regulation to lysosomal dysfunction, iron deficiency, and oxidative stress. |
format | Online Article Text |
id | pubmed-7433747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-74337472020-08-18 Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay Zhu, Xiaoqiang Zhang, He Mendell, Joshua T. Cell Rep Article Nonsense-mediated decay (NMD) is a pathway that degrades mRNAs containing premature termination codons. Here we describe a genome-wide screen for NMD factors that uncovers an unexpected mechanism that broadly governs 3′ untranslated region (UTR)-directed regulation. The screen reveals that NMD requires lysosomal acidification, which allows transferrin-mediated iron uptake, which, in turn, is necessary for iron-sulfur (Fe-S) cluster biogenesis. This pathway maintains the activity of the Fe-S cluster-containing ribosome recycling factor ABCE1, whose impaired function results in movement of ribosomes into 3′ UTRs, where they displace exon junction complexes, abrogating NMD. Importantly, these effects extend beyond NMD substrates, with ABCE1 activity required to maintain the accessibility of 3′ UTRs to diverse regulators, including microRNAs and RNA binding proteins. Because of the sensitivity of the Fe-S cluster of ABCE1 to iron availability and reactive oxygen species, these findings reveal an unanticipated vulnerability of 3′ UTR-directed regulation to lysosomal dysfunction, iron deficiency, and oxidative stress. 2020-07-14 /pmc/articles/PMC7433747/ /pubmed/32668236 http://dx.doi.org/10.1016/j.celrep.2020.107895 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Zhu, Xiaoqiang Zhang, He Mendell, Joshua T. Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay |
title | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay |
title_full | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay |
title_fullStr | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay |
title_full_unstemmed | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay |
title_short | Ribosome Recycling by ABCE1 Links Lysosomal Function and Iron Homeostasis to 3′ UTR-Directed Regulation and Nonsense-Mediated Decay |
title_sort | ribosome recycling by abce1 links lysosomal function and iron homeostasis to 3′ utr-directed regulation and nonsense-mediated decay |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433747/ https://www.ncbi.nlm.nih.gov/pubmed/32668236 http://dx.doi.org/10.1016/j.celrep.2020.107895 |
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