CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts.
Fiche publication
Date publication
janvier 2018
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent
Tous les auteurs :
Tabet R, Schaeffer L, Freyermuth F, Jambeau M, Workman M, Lee CZ, Lin CC, Jiang J, Jansen-West K, Abou-Hamdan H, Désaubry L, Gendron T, Petrucelli L, Martin F, Lagier-Tourenne C
Lien Pubmed
Résumé
Expansion of GC repeats in the C9ORF72 gene is the most prevalent inherited form of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded transcripts undergo repeat-associated non-AUG (RAN) translation producing dipeptide repeat proteins from all reading frames. We determined cis-factors and trans-factors influencing translation of the human C9ORF72 transcripts. GC translation operates through a 5'-3' cap-dependent scanning mechanism, requiring a CUG codon located upstream of the repeats and an initiator Met-tRNA. Production of poly-GA, poly-GP, and poly-GR proteins from the three frames is influenced by mutation of the same CUG start codon supporting a frameshifting mechanism. RAN translation is also regulated by an upstream open reading frame (uORF) present in mis-spliced C9ORF72 transcripts. Inhibitors of the pre-initiation ribosomal complex and RNA antisense oligonucleotides selectively targeting the 5'-flanking GC sequence block ribosomal scanning and prevent translation. Finally, we identified an unexpected affinity of expanded transcripts for the ribosomal subunits independently from translation.
Mots clés
Amyotrophic Lateral Sclerosis, genetics, C9orf72 Protein, biosynthesis, Cell Line, Dipeptides, genetics, Eukaryotic Initiation Factor-4F, genetics, Frameshifting, Ribosomal, genetics, Frontotemporal Dementia, genetics, HEK293 Cells, Humans, Microsatellite Repeats, genetics, Oligonucleotides, Antisense, genetics, Open Reading Frames, genetics, Peptide Chain Initiation, Translational, genetics, RNA, Antisense, genetics, RNA, Transfer, Met, genetics, Ribosomes, metabolism
Référence
Nat Commun. 2018 Jan 11;9(1):152