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TRNAMODI Report Summary

Project ID: 310489
Funded under: FP7-IDEAS-ERC
Country: Germany

Final Report Summary - TRNAMODI (The in vivo roles of tRNA modification)

Transfer RNA (tRNA) are the adapter molecules that link the amino acids to the genetic information encoded on a messenger RNA (mRNA). Interestingly, tRNA carry a plethora of chemical modifications that affect all aspects of tRNA biology. The absence of these modifications leads to the sensitivity against specific stress in single-cell eukaryotes and several degenerative diseases in humans. However, it was unclear how the lack of modifications asserts its phenotypes and induces pathologies. Furthermore, recent findings suggest that tRNA modifications may be used to regulate translation as a means to steer stress responses. The work of tRNAmodi sought to understand how the absence of tRNA modifications leads to phenotypes and whether these modifications are regulated. In order to do so, we set an emphasis on the establishment and further development of several state-of-the art methods. Hence, we used ribosome profiling to quantitatively characterize translation at codon resolution and RNA mass spectrometry to quantify levels of tRNA modifications.
We found that the absence of wobble uridine modifications led to the slowdown of specific codons during translation. Thus, cells became "dyslexic". Unexpectedly, this codon-specific translational slowdown triggers a failure of protein homeostasis emphasizing the importance of protein synthesis rates for their final quality. Our findings introduce a new paradigm into the interpretation of modification defects. In contrast to previous models we propose that defects in tRNA modifications lead to phenotypes through triggering global defects in cellular protein quality. Furthermore, it is likely that the same is true for different types of perturbation of the translation machinery. Hence, it will be important to analyze different pathologies in light of our findings. Finally, data obtained in yeast cells exposed to high temperatures suggest that modification rates change slowly and are unlikely to drive changes in gene expression but rather react to a changing environment.

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