Journal
EMBO JOURNAL
Volume 33, Issue 24, Pages 2947-2966Publisher
WILEY
DOI: 10.15252/embj.201488740
Keywords
neurodegeneration; RNA editing; RNA structure; splicing
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Funding
- NIH National Center for Research Resources
- NIH [NS063964, GM42432, AG026251, ES20395]
- DOD [W81XWH-10-1-0512-1, W81XWH-09-1-0315AL093108]
- CIHR Frederick Banting and Charles Best Canada Graduate Scholarship
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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 immuno-precipitable 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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