Identification of genes in toxicity pathways of trinucleotide-repeat RNA in C. elegans

Susana M.D.A. Garcia, Yuval Tabach, Guinevere F. Lourenço, Maria Armakola, Gary Ruvkun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Myotonic dystrophy disorders are caused by expanded CUG repeats in noncoding regions. Here we used Caenorhabditis elegans expressing CUG repeats to identify genes that modulate the toxicity of such repeats. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and that modulate formation of nuclear foci by CUG-repeat RNA. These genes regulate CUG repeat-induced toxicity through distinct mechanisms including RNA export and clearance, thus suggesting that CUG-repeat toxicity is mediated by multiple pathways. A subset of the genes are also involved in other degenerative disorders. The nonsense-mediated mRNA decay (NMD) pathway has a conserved role in regulating CUG-repeat-RNA transcript levels and toxicity, and NMD recognition of toxic RNAs depends on 3' €2-untranslated-region GC-nucleotide content. Our studies suggest a broader surveillance role for NMD in which variations in this pathway influence multiple degenerative diseases.

Original languageAmerican English
Pages (from-to)712-720
Number of pages9
JournalNature Structural and Molecular Biology
Volume21
Issue number8
DOIs
StatePublished - Aug 2014

Bibliographical note

Funding Information:
We thank M. Mahadevan (University of Virginia) for providing plasmids bearing the CUG repeats, S. Fischer and J. Kim for the RNAi library used in the screen, D. Kim (Massachusetts Institute of Technology) for the smg-2(qd101) strain and J. Lykke-Andersen (University of California, San Diego) for the mammalian antibody to UPF1. We are grateful to the J. Kaplan laboratory for the use of the Olympus FV-1000 confocal microscope and to the B. Seed lab for the use of their tissue-culture facilities. We are also thankful to S. Djonovic (Massachusetts General Hospital and Harvard Medical School) and S. Choi for reagents and technical assistance; J. Bai (Fred Hutchinson Cancer Research Center) for reagents, technical assistance and helpful discussions; A. Connery for help with the CellProfiler software; and J. Urbach for help editing the manuscript. We thank the Caenorhabditis elegans Genetics Center for strains; the American Heart Association (grant 0825938D) for funding S.M.D.A.G. and the US National Institutes of Health for funding G.R. (grant AG043184).

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