Grant: Operating Grant

Nature has developed mechanisms to protect living organisms against external intruders such as viruses, or internal dysfunction such as cancer. One such security mechanism is shutting down genes, also known as gene silencing. Gene silencing is at the heart of development and specialization. It has thus recently been widely used to study human and model organisms' genetics and development, and to create transgenic plants developing resistance to viruses. Increasing evidences suggest that diseases such as cancer are the result of multiple gene deregulations. A normal cellular reaction in front of such deregulations is shutting down these genes. However, in the case of cancer for unknown reasons, the cell is unable to do so and tumors develop and progress. We need to understanding better gene silencing mechanisms if we wish to discover why the cell cannot defends itself against cancer, or if we want to intervene efficiently in gene silencing to fight cancer. Gene silencing is based on a class of ribonucleic acids called microRNAs. One of the aims of this research proposal is to study the molecular basis of these microRNAs, and in particular the binding mechanism by which they bind the messenger RNAs of targeted genes. Predicting accurately the targeted genes of microRNAs is among the most important unresolved questions of gene silencing at this moment. Dr. Major proposes the application of an RNA computer-modeling framework he developed over the last 20 years to obtain high-resolution 3-D structures of microRNAs as well as of their targeted messenger RNAs. These 3-D structures will help him get insights into how and where microRNAs bind their targets, and prepare biological assays to confirm these insights.