TDP ‐1, the C aenorhabditis elegans ortholog of TDP ‐43, limits the accumulation of double‐stranded RNA

Abstract

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 RNA s 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 RNA s with inherent double‐stranded structure (ds RNA ); (2) increases the accumulation of nuclear ds RNA foci; (3) enhances the frequency of adenosine‐to‐inosine RNA editing; and (4) dramatically increases the amount of transcripts immunoprecipitable with a ds RNA ‐specific antibody, including intronic sequences, RNA s with antisense overlap to another transcript, and transposons. We also show that TDP ‐43 knockdown in human cells results in accumulation of ds RNA , indicating that suppression of ds RNA 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. image 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 RNA s, offering insight on the potential contribution of TDP ‐43/TDP‐1 to disease onset. TDP ‐1 acts co‐transcriptionally to limit the accumulation of ds RNA 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 ds RNA , potentially inducing an interferon response Human TDP ‐43 can act as an RNA chaperone in vitro