TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in 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.

journal_name

RNA Biol

journal_title

RNA biology

authors

Reverendo M,Soares AR,Pereira PM,Carreto L,Ferreira V,Gatti E,Pierre P,Moura GR,Santos MA

doi

10.4161/rna.32199

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

1199-213

issue

9

eissn

1547-6286

issn

1555-8584

journal_volume

11

pub_type

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