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Research interest

We are studying translation fidelity mechanisms in eukaryotes using a broad variety of approaches. Translation corresponds to the reading of the mRNA by ribosomes to obtain proteins.

Ribosomes are constituted by two ribonucleoprotein subunits acting cooperatively during translation of the mRNA. The small subunit (40S in eukaryotes) contains the mRNA binding site, the path along which the mRNA progresses, the decoding centre where codons are read by tRNAs. The large subunit (60S in eukaryotes) performs the peptide bond formation, and contains the polypeptide exit tunnel. tRNAs enter in the ribosome in the A-site, move to the P-site after peptide bond formation, and the deacetylated tRNA moves from the P-site to the E-site before to leave the ribosome. During each elongation cycle both subunits participate dynamically in translocating the mRNA and the tRNAs by 3 nucleotides.

A rich history of mechanistic studies has unravelled the essential process of protein synthesis. Despite all these studies translation fidelity has been less studied, and very little is known both at the structural and dynamics levels especially in eukaryotes.

Recoding signals are present on some mRNA and induce an alternative reading of the genetic code by diverting the standard rules. They are commonly found in retroviruses (HIV-1) or in coronaviruses (IBV, SARS), but are also found in cellular genes. These motifs are very efficient to disrupt the ribosome accuracy increasing error rate from background (< 5x10-5) to 50%. They represent powerful tools to study the mechanisms of translocation and reading frame maintenance. Understanding how these elements modify translation accuracy will reveal the mechanisms used by the ribosome to translate accurately the mRNA. To reach this objective we have developed in collaboration with Nathalie Westbrook and Karen Perronet from the Institut d’optic graduate school to setup a single molecule approach to study eukaryotic ribosome. This new system will allow us to follow ribosomes one by one to analyse rare and asynchronous events like recoding.

Recoding events also represent an important regulation step in gene expression. Indeed major cellular functions are under the control of recoding, indicating that this translational regulation is not limited to viruses. To identify such sites in genomes we use a variety of approaches ranging from the classical genetics and biochemical to the recently described ribosome profiling approach. This last approach allows to study translational regulations genome-wide at a resolution of one nucleotide! This powerful technics is broadly used in our projects to decipher genes regulations and to identify new coding regions. This is also an opportunity to collaborate with other teams interested in translational regulations.

Stop codon readthrough and therapeutical perspectives
Ten percent of inherited diseases are caused by premature termination codon (PTC) mutations that lead to degradation of the mRNA template and to the production of a non-functional, truncated polypeptide. In addition, many acquired mutations in cancer introduce similar PTC mutations. In 1999, proof-of-concept for treating these disorders was obtained in a mouse model of muscular dystrophy, when administration of aminoglycosides restored protein translation by inducing the ribosome to bypass a PTC. Since, many studies have validated this approach, but despite the promise of PTC readthrough therapies, the mechanisms of translation termination remain to be precisely elucidated before greater progress can be made. We are currently searching for new drugs stimulating stop codon readthrough and deciphering the link between stop codon readthrough and mRNA stability.