TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA.
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.
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA tassa.saldi@colorado.edu.
Tassa K
TK
Saldi
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Peter Ea
PE
Ash
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada Informatics and Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Gavin
G
Wilson
Institute for Behavioral Genetics University of Colorado, Boulder, CO, USA.
Patrick
P
Gonzales
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA.
Alfonso
A
Garrido-Lecca
Institute for Behavioral Genetics University of Colorado, Boulder, CO, USA.
Christine M
CM
Roberts
Institute for Behavioral Genetics University of Colorado, Boulder, CO, USA.
Vishantie
V
Dostal
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Tania F
TF
Gendron
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Lincoln D
LD
Stein
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA.
Thomas
T
Blumenthal
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Leonard
L
Petrucelli
Institute for Behavioral Genetics University of Colorado, Boulder, CO, USA Integrative Physiology, University of Colorado, Boulder, CO, USA.
Christopher D
CD
Link
D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D020871:RNA Stability; D012330:RNA, Double-Stranded / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; C000595270:TDP-1 protein, C elegans
RNA editing; RNA structure; neurodegeneration; splicing