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Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression
Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohume...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592454/ https://www.ncbi.nlm.nih.gov/pubmed/37314931 http://dx.doi.org/10.1016/j.celrep.2023.112642 |
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author | Campbell, Amy E. Dyle, Michael C. Albanese, Roberto Matheny, Tyler Sudheendran, Kavitha Cortázar, Michael A. Forman, Thomas Fu, Rui Gillen, Austin E. Caruthers, Marvin H. Floor, Stephen N. Calviello, Lorenzo Jagannathan, Sujatha |
author_facet | Campbell, Amy E. Dyle, Michael C. Albanese, Roberto Matheny, Tyler Sudheendran, Kavitha Cortázar, Michael A. Forman, Thomas Fu, Rui Gillen, Austin E. Caruthers, Marvin H. Floor, Stephen N. Calviello, Lorenzo Jagannathan, Sujatha |
author_sort | Campbell, Amy E. |
collection | PubMed |
description | Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated. |
format | Online Article Text |
id | pubmed-10592454 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-105924542023-10-23 Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression Campbell, Amy E. Dyle, Michael C. Albanese, Roberto Matheny, Tyler Sudheendran, Kavitha Cortázar, Michael A. Forman, Thomas Fu, Rui Gillen, Austin E. Caruthers, Marvin H. Floor, Stephen N. Calviello, Lorenzo Jagannathan, Sujatha Cell Rep Article Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated. 2023-06-27 2023-06-13 /pmc/articles/PMC10592454/ /pubmed/37314931 http://dx.doi.org/10.1016/j.celrep.2023.112642 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Campbell, Amy E. Dyle, Michael C. Albanese, Roberto Matheny, Tyler Sudheendran, Kavitha Cortázar, Michael A. Forman, Thomas Fu, Rui Gillen, Austin E. Caruthers, Marvin H. Floor, Stephen N. Calviello, Lorenzo Jagannathan, Sujatha Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression |
title | Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression |
title_full | Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression |
title_fullStr | Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression |
title_full_unstemmed | Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression |
title_short | Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression |
title_sort | compromised nonsense-mediated rna decay results in truncated rna-binding protein production upon dux4 expression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592454/ https://www.ncbi.nlm.nih.gov/pubmed/37314931 http://dx.doi.org/10.1016/j.celrep.2023.112642 |
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