Structure and Function of Nucleic Acids

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): The long term goal is to be able to correctly predict from its sequence (1) how an RNA folds into its biologically functional form, (2) how its structure affects its function, and (3) how fast it folds and responds to proteins and other ligands in its environment. RNA molecules are crucial in all aspects of gene expression. Messenger RNAs transfer the genetic information in DNA;in RNA viruses the RNA is both the genetic information, and the messenger for protein synthesis. Non-coding RNAs, including microRNAs and small interfering RNAs, regulate transcription of DNA to RNA and translation of RNA to protein. Errors in processing and control of messenger RNAs are linked to human diseases, including neurodegenerative diseases such as Lou Gehrig's disease. RNAs are being investigated as inhibitors of messenger RNAs to silence specific genes, and to cure diseases. RNAs both human and viral are also outstanding targets for drugs to prevent or cure human diseases. 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 RNA as drugs and as targets for drugs. In order to obtain this knowledge, RNA molecules are synthesized in the laboratory by RNA polymerase from a DNA template. A micron-sized bead is attached to each end of a single RNA molecule;one bead is held in a micropipette, the other in a laser trap. By moving the micropipette, the RNA molecule is unfolded. The distance (nanometers) between the beads and the force (piconewtons) on the bead in the laser trap are measured. These data provide the thermodynamic stability of the RNA, and its rates of unfolding and refolding. The effects of proteins that unwind, transcribe, and translate the RNA, as well as drugs that inhibit these processes are determined. 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 human diseases. RNA viruses cause many human diseases including AIDS, flu, hepatitis C, SARS, etc. Malfunctioning RNAs that occur naturally in humans can also cause diseases. Investigation of RNA structure will provide better understanding of RNA function, and can lead to better drugs to cure or prevent human disease.