Grant: Operating Grant

RNA controls gene expression through a number of different mechanisms, and disruption of RNA-dependent events are associated with several human diseases, including developmental aberrations, pathogenic infections and cancer. Over the last several years, we have focused on structure-function studies of two types of functional RNAs: ribozymes and riboswitches. Ribozymes are RNA enzymes that cleave specific RNA sequences and, thus, have the potential to be engineered to inactivate target genes. Riboswitches are RNA regulatory elements that modulate gene expression in response to metabolite binding. Most riboswitches have been found in bacteria and, thus, represent ideal targets for the development of new antibiotics against pathogenic bacteria. The overall objective of this proposal is to continue our structure-function studies of ribozymes and riboswiches in order to help develop RNA-based therapeutics and diagnostic agents. More specifically, we propose to 1) Structurally investigate the Neurospora VS ribozyme; 2) Engineer VS-derived ribozymes; and 3) Structurally investigate the interaction between purine riboswitches and agonists with antibiotic properties. Our proposed investigations will reveal important structure-function aspects of both purine riboswitches and the VS ribozyme. In addition, they will assist in the development of novel antibiotics that target RNA and help derive principles of RNA engineering that will be valuable in the development of RNA-based tools for biochemical and biomedical applications.