Structure and Function of Nucleic Acids

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DESCRIPTION (provided by applicant): The long term goal is to be able to deduce a three-dimensional structure for an RNA molecule solely from the sequence of its bases. Small interfering RNAs and micro RNAs help regulate gene expression. Messenger RNA molecules transfer and interpret the genetic information in DNA to produce proteins. Ribosomal RNAs and transfer RNAs are key parts of the machinery necessary to synthesize the proteins. Errors in RNA processing, in control of messenger RNA translation, and in control of messenger RNA lifetimes are linked to many human diseases, including several neurodegenerative diseaeses such as Lou Gehrig's disease. In RNA viruses, the RNA is both the genetic information, and the messenger for protein synthesis. Thus, naturally occurring RNAs and viral RNAs are outstanding targets for drugs to prevent or cure disease. The overwhelming majority of drug targets up to now have been proteins, so RNA provides major new opportunities. Knowledge of the three-dimensional structures of RNAs, their stabilities, and their rates of interconversion is crucial to understanding RNA function, and is key to developing anti-RNA drugs. In order to obtain this knowledge, RNA molecules are synthesized in the laboratory by RNA potymerase from a DNA template. A bead is attached to each end of a single RNA molecule; one bead is held in a micropipet, the other in a laser trap. By moving the micropipet, the RNA molecule is unfolded The distance (nanometers) between the beads and the force (piconewtons) on the bead in the laser trap is measured. These data provide the thermodynamic stabilities of the folded RNA (secondary and tertiary structures) relative to the unfolded single strand. The rates of unfolding and refolding are also measured. This information will lead to improved understanding of RNA structure, stability, and dynamics. It will help in understanding RNA function, and in controlling the role of RNA in viral and genetic diseases