Wobble transfer RNA modifications optimize dynamic proteome expression
In an article published in Nature Communications, Dr Francesca Rapino & Dr Pierre Close, from the cancer signaling laboratory of GIGA ULIEGE, discover how the regulation of transfer RNAs and modification of their anticodon impact the dynamics of protein synthesis and regulate protein folding and stability.
The study of the genetic mutations responsible for the formation of cancers has led to the development of new drugs that specifically target cancer cells and which significantly improve the prognosis of patients. However, tumor development also involves a series of non-genetic mechanisms that allow cancer cells to adapt and escape therapy. The regulation of protein synthesis appears to be a central mechanism allowing the adaptation and reprogramming of cancer cells during tumor development. Recent work by Dr Pierre Close's team has demonstrated the importance of the regulation of transfer RNAs (tRNAs) in the growth, invasion and therapeutic resistance of cancers, by regulating protein synthesis.
In this study, the team set out to investigate the mechanisms underlying the reprogramming of protein synthesis through the regulation of tRNAs. The synthesis of new proteins is a highly regulated process that is responsible for the expression of all the proteins present in a cell, in a given context. During protein synthesis, messenger RNAs (mRNAs) are translated into proteins, via adaptor molecules, tRNAs which, within the ribosomes, ensure recognition of the codon sequence of mRNAs and add the corresponding amino acid to the nascent peptide chain.
In order to ensure optimal translation and protein synthesis under the best conditions, the tRNAs are modified at their anticodon. In particular, the modifications at their wobble base make it possible to ensure perfect fidelity in the translation of mRNAs by tRNAs. A lack of fidelity during translation results in problems in protein folding, which leads to their subsequent aggregation and degradation.
In this study, the role of the modification of the tRNAs on the uridines located at the wobble base of the anticodon (U34-tRNA), which is catalyzed by an enzymatic cascade enclosing among others the enzymes ELONGATOR and CTU1 / CTU2 was studied in more details. The results have shed light on the mechanisms that link the regulation of translation by tRNA modification to protein stability and expression. Surprisingly, it has been discovered that a large majority of genes are insensitive to U34-tRNA modifications. On the other hand, for a certain number of genes, these modifications are essential during their translation, otherwise, the proteins produced are unstable and are degraded. It appears that the presence of specific sequences of hydrophilic amino acids, when combined with a slowdown in translation, precipitates proteins towards aggregation and leads to their degradation.
These results provide key insights into the impact of the regulation of translation by tRNA modification on protein stability and function. This work makes it possible to envision a more systematic prediction of the identity of proteins whose expression depends on the regulation of the numerous modifications of tRNAs. Conceptually, this will allow a more precise identification of the different cellular vulnerabilities towards the regulation of mRNA translation and tRNA modifications, based on the set of proteins expressed by the cells.
Contact
Maître de Recherche FNRS
Contact
Maître de Recherche FNRS
Investigateur WELBIO
Laboratory of Cancer Signaling
Reference
Francesca Rapino*, Zhaoli Zhou*, Ana Maria Roncero Sanchez*, Marc Joiret, Christian Seca, Najla El Hachem, Gianluca Valenti, Sara Latini, Kateryna Shostak, Liesbet Geris, Ping Li, Gang Huang, Gabriel Mazzucchelli, Dominique Baiwir, Christophe J. Desmet, Alain Chariot, Michel Georges, and Pierre Close. Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate, Nature Communications, 2021.
WELBIO
Laboratory of Cancer Signaling
Référence
Francesca Rapino*, Zhaoli Zhou*, Ana Maria Roncero Sanchez*, Marc Joiret, Christian Seca, Najla El Hachem, Gianluca Valenti, Sara Latini, Kateryna Shostak, Liesbet Geris, Ping Li, Gang Huang, Gabriel Mazzucchelli, Dominique Baiwir, Christophe J. Desmet, Alain Chariot, Michel Georges, and Pierre Close. Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate, Nature Communications, 2021.
