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Open Access Research article

Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast

João A Paredes1, Laura Carreto1, João Simões1, Ana R Bezerra1, Ana C Gomes1, Rodrigo Santamaria2, Misha Kapushesky2, Gabriela R Moura1 and Manuel AS Santos1*

Author Affiliations

1 RNA Biology Laboratory, Department of Biology and CESAM, University of Aveiro, 3810-193 Aveiro, Portugal

2 European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD Cambridge, UK

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BMC Biology 2012, 10:55  doi:10.1186/1741-7007-10-55

Published: 20 June 2012

Abstract

Background

Organisms use highly accurate molecular processes to transcribe their genes and a variety of mRNA quality control and ribosome proofreading mechanisms to maintain intact the fidelity of genetic information flow. Despite this, low level gene translational errors induced by mutations and environmental factors cause neurodegeneration and premature death in mice and mitochondrial disorders in humans. Paradoxically, such errors can generate advantageous phenotypic diversity in fungi and bacteria through poorly understood molecular processes.

Results

In order to clarify the biological relevance of gene translational errors we have engineered codon misreading in yeast and used profiling of total and polysome-associated mRNAs, molecular and biochemical tools to characterize the recombinant cells. We demonstrate here that gene translational errors, which have negligible impact on yeast growth rate down-regulate protein synthesis, activate the unfolded protein response and environmental stress response pathways, and down-regulate chaperones linked to ribosomes.

Conclusions

We provide the first global view of transcriptional and post-transcriptional responses to global gene translational errors and we postulate that they cause gradual cell degeneration through synergistic effects of overloading protein quality control systems and deregulation of protein synthesis, but generate adaptive phenotypes in unicellular organisms through activation of stress cross-protection. We conclude that these genome wide gene translational infidelities can be degenerative or adaptive depending on cellular context and physiological condition.

Keywords:
Yeast; mistranslation; tRNA; protein synthesis; mRNA profiling; stress; proteotoxic stress; protein misfolding; unfolded protein response