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 language | English |
|---|---|
| Pages (from-to) | 712-720 |
| Number of pages | 9 |
| Journal | Nature Structural and Molecular Biology |
| Volume | 21 |
| Issue number | 8 |
| DOIs | |
| State | Published - 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).