Messenger RNA splicing is a fundamental process in message maturation to ensure translation of the appropriate protein product in eukaryotic cells. Its failure,misplicing, is implicated in a range of human diseases (i.e. Alzheimer’s, cystic fibrosis and various cancers). In order to better understand the inner workings of misplicing, the mechanism of splicing has to be understood at the molecular level. To perform this task, we are investigating the structural biology of a model system, the group II intron, to identify its catalytic mechanism and its key molecular players.
- Gene Expression Regulation
Gene regulation was long thought to be a purely protein-driven process. However, this past decade it was proven that RNA alone plays also a major role in regulation of gene expression at both the transcriptional and translational level. For instance, many cases have been observed where the 5’ untranslated region of an mRNA acts as a sensor of small metabolites producing a change in the RNA’s conformation that could up- or down-regulate expression of the gene downstream. In our lab, we investigate a series of these riboswitches and other regulatory RNA elements to unveil the structural and dynamic basis for their ability to regulate gene activity.
Aminoglycosides and macrolides are known to interact with ribosomal RNA to exert their antibiotic effects. As in these two examples and with increasing evidence of RNA as gene regulators, efforts at new drug discovery and design are focusing not only at targeting proteins and DNAs but also RNAs. Some act within macromolecular complexes such as the ribosome, while others likely act within smaller regulatory components such as riboswitches. Therefore, a major effort underway in our lab is screening for various drugs and drug targets that fall within these categories using structure assisted approaches. Later, these RNA-drug complexes could be potentially useful in pre-clinical studies.