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

• Published in: The EMBO journal 2014-12, Vol.33 (24), p.2947-2966
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Accumulation; Animals; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; EMBO36; Gene Deletion; Gene Expression Profiling; Genotype & phenotype; Humans; Microbiology; Mutation; Nematodes; neurodegeneration; Proteins; Ribonucleic acid; RNA; RNA editing; RNA Stability; RNA structure; RNA, Double-Stranded - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; splicing
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201488740

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. Synopsis Mutations in RNA‐binding protein TDP‐43 are linked to ALS. This study reports that the worm homolog of TDP‐43, TDP‐1, limits the accumulation of double‐stranded RNAs, offering insight on the potential contribution of TDP‐43/TDP‐1 to disease onset. TDP‐1 acts co‐transcriptionally to limit the accumulation of dsRNA TDP‐1 limits A‐to‐I RNA editing TDP‐1 maintains chemotaxis by limiting the action of RNA interference Knockdown of TDP‐43 in human cells leads to an increase in dsRNA, potentially inducing an interferon response Human TDP‐43 can act as an RNA chaperone in vitro Graphical Abstract Mutations in RNA‐binding protein TDP‐43 are linked to ALS. This study reports that the worm homolog of TDP‐43, TDP‐1, limits the accumulation of double‐stranded RNAs, offering insight on the potential contribution of TDP‐43/TDP‐1 to disease onset.