Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast.
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.
RNA Biology Laboratory, Department of Biology and CESAM, University of Aveiro, Aveiro, Portugal.
João A
JA
Paredes
Laura
L
Carreto
João
J
Simões
Ana R
AR
Bezerra
Ana C
AC
Gomes
Rodrigo
R
Santamaria
Misha
M
Kapushesky
Gabriela R
GR
Moura
Manuel A S
MA
Santos
D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D014176:Protein Biosynthesis; D058767:Protein Unfolding; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D059467:Transcriptome; D015003:Yeasts / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
D005656:Fungal Proteins; D012331:RNA, Fungal; D012343:RNA, Transfer