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Structure-function relationship of RNA

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RNA, by virtue of its physicochemical properties (structural, catalytic), plays an essential role in the maintenance of cellular homeostasis, whether for example at the level of protein synthesis or genetic regulation. Like proteins, RNA molecules must adopt a precise three-dimensional structure, and sometimes very complex, to be able to exert their particular function (eg ribosomal RNA). Despite the recent technological advances in molecular biology and bioinformatics, it is still impossible to accurately predict the temporal and three-dimensional folding of an RNA.

In order to better understand the dynamics surrounding these folding steps, our laboratory focused for a long time on the exhaustive study of a self-catalytic RNA motif naturally found in the genome of the human hepatitis delta virus. This small motif, the HDV ribozyme, is an excellent model for studying the structure-function relationship of RNA. Any change in the nucleotide identity of its primary sequence has a direct influence on the tertiary structure of the HDV ribozyme and, therefore, on the reaction path leading to catalysis. Several techniques have been used in the laboratory to dissect and modulate the folding pathway of this RNA such as: cross-linking experiments, fluorescence, mutagenesis, enzymatic kinetics, circular dichroism, in vitro selection, microcalorimetry, in silico modeling, etc. The HDV ribozyme folding pathway remains to date the best described among the RNA molecules.

The results of our work allowed us to highlight the basic rules governing the folding of nucleic acids. In the long term, these elementary rules can be used to accurately predict the folding of a particular RNA and, consequently, allow us to molecularly modulate the structure-function of this RNA. We have also developed ribozymes whose activities are modulated by different chemical molecules such as oligonucleotides and metabolites.