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TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA

Caenorhabditis elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA-binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these t...

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Autores principales: Saldi, Tassa K, Ash, Peter EA, Wilson, Gavin, Gonzales, Patrick, Garrido-Lecca, Alfonso, Roberts, Christine M, Dostal, Vishantie, Gendron, Tania F, Stein, Lincoln D, Blumenthal, Thomas, Petrucelli, Leonard, Link, Christopher D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282642/
https://www.ncbi.nlm.nih.gov/pubmed/25391662
http://dx.doi.org/10.15252/embj.201488740
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author Saldi, Tassa K
Ash, Peter EA
Wilson, Gavin
Gonzales, Patrick
Garrido-Lecca, Alfonso
Roberts, Christine M
Dostal, Vishantie
Gendron, Tania F
Stein, Lincoln D
Blumenthal, Thomas
Petrucelli, Leonard
Link, Christopher D
author_facet Saldi, Tassa K
Ash, Peter EA
Wilson, Gavin
Gonzales, Patrick
Garrido-Lecca, Alfonso
Roberts, Christine M
Dostal, Vishantie
Gendron, Tania F
Stein, Lincoln D
Blumenthal, Thomas
Petrucelli, Leonard
Link, Christopher D
author_sort Saldi, Tassa K
collection PubMed
description Caenorhabditis elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA-binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP-1 is to limit formation or stability of double-stranded RNA. Specifically, we found that deletion of tdp-1: (1) preferentially alters the accumulation of RNAs with inherent double-stranded structure (dsRNA); (2) increases the accumulation of nuclear dsRNA foci; (3) enhances the frequency of adenosine-to-inosine RNA editing; and (4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA-specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP-43 knockdown in human cells results in accumulation of dsRNA, indicating that suppression of dsRNA is a conserved function of TDP-43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP-43 function.
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spelling pubmed-42826422015-01-14 TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA Saldi, Tassa K Ash, Peter EA Wilson, Gavin Gonzales, Patrick Garrido-Lecca, Alfonso Roberts, Christine M Dostal, Vishantie Gendron, Tania F Stein, Lincoln D Blumenthal, Thomas Petrucelli, Leonard Link, Christopher D EMBO J Articles Caenorhabditis elegans mutants deleted for TDP-1, an ortholog of the neurodegeneration-associated RNA-binding protein TDP-43, display only mild phenotypes. Nevertheless, transcriptome sequencing revealed that many RNAs were altered in accumulation and/or processing in the mutant. Analysis of these transcriptional abnormalities demonstrates that a primary function of TDP-1 is to limit formation or stability of double-stranded RNA. Specifically, we found that deletion of tdp-1: (1) preferentially alters the accumulation of RNAs with inherent double-stranded structure (dsRNA); (2) increases the accumulation of nuclear dsRNA foci; (3) enhances the frequency of adenosine-to-inosine RNA editing; and (4) dramatically increases the amount of transcripts immunoprecipitable with a dsRNA-specific antibody, including intronic sequences, RNAs with antisense overlap to another transcript, and transposons. We also show that TDP-43 knockdown in human cells results in accumulation of dsRNA, indicating that suppression of dsRNA is a conserved function of TDP-43 in mammals. Altered accumulation of structured RNA may account for some of the previously described molecular phenotypes (e.g., altered splicing) resulting from reduction of TDP-43 function. Blackwell Publishing Ltd 2014-12-17 2014-11-12 /pmc/articles/PMC4282642/ /pubmed/25391662 http://dx.doi.org/10.15252/embj.201488740 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Saldi, Tassa K
Ash, Peter EA
Wilson, Gavin
Gonzales, Patrick
Garrido-Lecca, Alfonso
Roberts, Christine M
Dostal, Vishantie
Gendron, Tania F
Stein, Lincoln D
Blumenthal, Thomas
Petrucelli, Leonard
Link, Christopher D
TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA
title TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA
title_full TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA
title_fullStr TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA
title_full_unstemmed TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA
title_short TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA
title_sort tdp-1, the caenorhabditis elegans ortholog of tdp-43, limits the accumulation of double-stranded rna
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282642/
https://www.ncbi.nlm.nih.gov/pubmed/25391662
http://dx.doi.org/10.15252/embj.201488740
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