Evolution of Catalytic RNAs towards RNA-protein Catalysts

University Of California-San Diego, La Jolla CA

Investigators

Abstract

The RNA world hypothesis states that the early evolution of life went through a stage in which RNA served both as genome and catalyst. The long-term goal of this project is to re-create an RNA world in the laboratory. Towards establishing such a self-replicating RNA system, a catalytic RNA (ribozyme) was developed previously that catalyzes RNA polymerization. However, the polymerization efficiency of this ribozyme is about 100-fold lower than what is required for self-replication, limited by a low substrate affinity. Attempts to improve the efficiency of the polymerase ribozyme by in vitro evolution have so far led to only small improvements. In contrast, recent experiments have shown that hydrophobic cofactors associated with the ribozyme and its substrate are able to improve polymerization efficiency by 3- to 20-fold. This result and the analogy to biological RNAs sparked the idea to search for even better non-RNA cofactors in the form of amino acids and peptides. Combinations of design and in vitro evolution will be used to obtain cofactor dependent ribozymes. Analysis of these ribozymes will help to understand how amino acids and peptides can assist RNAs, on a functional, structural and evolutionary level. Additionally, the recapitulation of life's origin in the laboratory will show how life may have originated during the early history of the planet. The PI is teaching in classroom settings to undergraduates and graduates, is providing research training graduate and undergraduate students in the laboratory, is hosting students from Rancho Bernardo High School in his lab during the summer, and in a pilot project, is mentoring UCSD transfer students from the Thurgood-Marshall College.