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

• Tassa K Saldi ^[1] ; Peter EA Ash ^[3] ; Gavin Wilson ^[2] ; Patrick Gonzales ^[1] ; Alfonso Garrido-Lecca ^[1] ; Christine M Roberts ^[1] ; Vishantie Dostal ^[1] ; Tania F Gendron ^[3] ; Lincoln D Stein ^[2] ; Thomas Blumenthal ^[1] ; Leonard Petrucelli ^[3] ; Christopher D Link ^[4]
  1. [1] University of Colorado Boulder

     University of Colorado Boulder

     Estados Unidos

     
  2. [2] University of Toronto

     University of Toronto

     Canadá

     
  3. [3] 2 Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA
  4. [4] 5 Institute for Behavioral Genetics, University of Colorado Boulder, CO, USA; 6 Integrative Physiology, University of Colorado Boulder, CO, USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 33, Nº. 24, 2014, págs. 2947-2966
• Idioma: inglés
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• Resumen

  • 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.