PUBLICATION
TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish
- Authors
- Reverendo, M., Soares, A.R., Pereira, P.M., Carreto, L., Ferreira, V., Gatti, E., Pierre, P., Moura, G.R., Santos, M.A.
- ID
- ZDB-PUB-141209-16
- Date
- 2014
- Source
- RNA Biology 11(9): 1199-213 (Journal)
- Registered Authors
- Pereira, Patricia, Santos, Manuel
- Keywords
- ROS, mRNA mistranslation, protein aggregation, proteotoxic stress, tRNA, zebrafish
- MeSH Terms
-
- Animals
- Blotting, Northern
- Blotting, Western
- Cell Nucleus/genetics
- Codon/genetics*
- DNA Damage/genetics
- DNA, Mitochondrial/genetics
- Embryo, Nonmammalian/cytology*
- Embryo, Nonmammalian/physiology
- Endoplasmic Reticulum/metabolism
- Mutation/genetics*
- Oxidative Stress
- Proteasome Endopeptidase Complex/genetics
- Protein Biosynthesis*
- Protein Processing, Post-Translational
- Proteins/metabolism*
- Proteome/analysis
- RNA, Transfer/genetics*
- Reactive Oxygen Species/metabolism
- Unfolded Protein Response/physiology
- Zebrafish/embryology
- Zebrafish/genetics*
- PubMed
- 25483040 Full text @ RNA Biol.
Citation
Reverendo, M., Soares, A.R., Pereira, P.M., Carreto, L., Ferreira, V., Gatti, E., Pierre, P., Moura, G.R., Santos, M.A. (2014) TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish. RNA Biology. 11(9):1199-213.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping