TY - JOUR
T1 - TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA
AU - Saldi, Tassa K.
AU - Ash, Peter E.A.
AU - Wilson, Gavin
AU - Gonzales, Patrick
AU - Garrido-Lecca, Alfonso
AU - Roberts, Christine M.
AU - Dostal, Vishantie
AU - Gendron, Tania F.
AU - Stein, Lincoln D.
AU - Blumenthal, Thomas
AU - Petrucelli, Leonard
AU - Link, Christopher D.
N1 - Publisher Copyright:
© 2014 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2014/12/17
Y1 - 2014/12/17
N2 - 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 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.
AB - 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 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.
KW - RNA editing
KW - RNA structure
KW - neurodegeneration
KW - splicing
UR - http://www.scopus.com/inward/record.url?scp=84918825214&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84918825214&partnerID=8YFLogxK
U2 - 10.15252/embj.201488740
DO - 10.15252/embj.201488740
M3 - Article
C2 - 25391662
AN - SCOPUS:84918825214
SN - 0261-4189
VL - 33
SP - 2947
EP - 2966
JO - EMBO Journal
JF - EMBO Journal
IS - 24
ER -