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title TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish
authors Reverendo, M; Soares, AR; Pereira, PM; Carreto, L; Ferreira, V; Gatti, E; Pierre, P; Moura, GR; Santos, MA
author full name Reverendo, Marisa; Soares, Ana R.; Pereira, Patricia M.; Carreto, Laura; Ferreira, Violeta; Gatti, Evelina; Pierre, Philippe; Moura, Gabriela R.; Santos, Manuel A.
title TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish
nationality nacional
language English
document type Article
author keywords tRNA; mRNA mistranslation; proteotoxic stress; protein aggregation; ROS; zebrafish
abstract Mutations in genes that encode tRNAs, aminoacyl-tRNA syntheases, tRNA modifying enzymes and other tRNA interacting partners are associated with neuropathies, cancer, type-II diabetes and hearing loss, but how these mutations cause disease is unclear. We have hypothesized that levels of tRNA decoding error (mistranslation) that do not fully impair embryonic development can accelerate cell degeneration through proteome instability and saturation of the proteostasis network. To test this hypothesis we have induced mistranslation in zebrafish embryos using mutant tRNAs that misincorporate Serine (Ser) at various non-cognate codon sites. Embryo viability was affected and malformations were observed, but a significant proportion of embryos survived by activating the unfolded protein response (UPR), the ubiquitin proteasome pathway (UPP) and downregulating protein biosynthesis. Accumulation of reactive oxygen species (ROS), mitochondrial and nuclear DNA damage and disruption of the mitochondrial network, were also observed, suggesting that mistranslation had a strong negative impact on protein synthesis rate, ER and mitochondrial homeostasis. We postulate that mistranslation promotes gradual cellular degeneration and disease through protein aggregation, mitochondrial dysfunction and genome instability.
author address [Reverendo, Marisa; Soares, Ana R.; Pereira, Patricia M.; Carreto, Laura; Ferreira, Violeta; Moura, Gabriela R.; Santos, Manuel A.] Univ Aveiro, iBiMED & Hlth Sci, Aveiro, Portugal; [Gatti, Evelina; Pierre, Philippe] Aix Marseille Univ, Ctr Immunol Marseille Luminy, Marseille, France; [Gatti, Evelina; Pierre, Philippe] INSERM, F-13258 Marseille, France; [Gatti, Evelina; Pierre, Philippe] CNRS, Marseille, France
reprint address Santos, MA (reprint author), Univ Aveiro, iBiMED & Hlth Sci, Aveiro, Portugal.
e-mail address msantos@ua.pt
funding agency and grant number Portuguese Foundation for Science and Technology (FCT) [FCT-ANR/IMI-MIC/0041/2012, SFRH/BD/47868/2008]
funding text The authors are most grateful to the Portuguese Foundation for Science and Technology (FCT) for funding our work through project No FCT-ANR/IMI-MIC/0041/2012, SFRH/BD/47868/2008 to M.R. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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cited reference count 85
publisher city AUSTIN
publisher address 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA
issn 1547-6286
29-character source abbreviation RNA BIOL
iso source abbreviation RNA Biol.
publication date SEP
year published 2014
volume 11
issue 9
beginning page 1199
ending page 1213
digital object identifier (doi) 10.4161/rna.32199
page count 15
web of science category Biochemistry & Molecular Biology
subject category Biochemistry & Molecular Biology
document delivery number AZ8KE
unique article identifier WOS:000348463500012
CESAM authors