Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats
Author:
Tseng Yi-Ju,Malik Indranil,Deng Xiexiong,Krans Amy,Jansen-West Karen,Tank Elizabeth M.H.,Gomez Nicolas B.,Sher Roger,Petrucelli Leonard,Barmada Sami J.,Todd Peter K.
Abstract
ABSTRACTA GGGGCC (G4C2) hexanucleotide repeat expansion inC9ORF72causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion inFMR1leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1, and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter cell lines and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation - suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation elongation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.Graphical Abstract
Publisher
Cold Spring Harbor Laboratory
Reference137 articles.
1. Nelson, D.L. , Orr, H.T. and Warren, S.T . (2013) The unstable repeats-Three evolving faces of neurological disease. Neuron, 77. 2. Koob, M.D. , Moseley, M.L. , Schut, L.J. , Benzow, K.A. , Bird, T.D. , Day, J.W. and Ranum, L.P.W . (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet, 21. 3. Correction: Initial sequencing and analysis of the human genome 4. Liquori, C.L. , Ricker, K. , Moseley, M.L. , Jacobsen, J.F. , Kress, W. , Naylor, S.L. , Day, J.W. and Ranum, L.P.W . (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron I of ZNF9. Science (1979), 293. 5. Verkerk, A.J.M.H. , Pieretti, M. , Sutcliffe, J.S. , Fu, Y.H. , Kuhl, D.P.A. , Pizzuti, A. , Reiner, O. , Richards, S. , Victoria, M.F. , Zhang, F. , et al. (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell, 65.
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