title: Identification of genes in toxicity pathways of trinucleotide-repeat RNA in C. elegans.
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'-untranslated-region GC-nucleotide content. Our studies suggest a broader surveillance role for NMD in which variations in this pathway influence multiple degenerative diseases.
authors.affiliation: 1] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Susana M D A
authors.initials: SM
authors.lastname: Garcia
authors.affiliation: 1] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Tabach
authors.affiliation: 1] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [3].
authors.forename: Guinevere F
authors.initials: GF
authors.lastname: Lourenço
authors.affiliation: 1] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Armakola
authors.affiliation: 1] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Ruvkun
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017124:Conserved Sequence; D005347:Fibroblasts / Q000378:metabolism; D017238:Genes, Helminth; D006801:Humans; D008124:Locomotion; D009132:Muscles / Q000002:abnormalities; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics; D059365:Nonsense Mediated mRNA Decay; D018510:RNA, Helminth / Q000235:genetics* / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: D020413:3' Untranslated Regions; D029742:Caenorhabditis elegans Proteins; D018510:RNA, Helminth