Date of Award

Spring 1-1-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Michael Yarus

Second Advisor

Norman Pace

Third Advisor

Rob Knight

Abstract

Ribonucleic acid (RNA) has the ability to store and transfer genetic information, and also to catalyze chemical reactions. This observation has led to the RNA world hypothesis, which states that there was likely a time in early evolution (before DNA and proteins) in which RNA carried out both these functions. In particular, RNA may have played an important role in the origin of protein (peptide) synthesis, or translation. While modern protein synthesis requires protein catalysis or stabilization at each of the relevant chemical steps, RNA is the functional heart of the ribosome. There must have been a mechanism in place to synthesize the first proteins, which logically could not have been protein-catalyzed. Early proteins, then, may have been synthesized by RNA catalysts. Most previously characterized RNA enzymes, or ribozymes, are relatively complex. This makes their existence in the early RNA world problematic, since even RNA synthesis must have been relatively inefficient. In this work, I show that a ribozyme that is only five nucleotides long can catalyze one of the reactions relevant to protein synthesis, aminoacylation of an RNA substrate, using the same reactants that biology uses today. In addition, this ribozyme/substrate complex hosts the formation of RNA-peptides and aminoacyl- and peptidyl-RNA diesters. In addition, no ribozymes have been found which catalyze the final crucial step of protein synthesis, peptide bond formation. I approach this problem by showing that RNAs that bind specifically to a dipeptide can be derived through in vitro selection. Therefore, RNAs can bind to two amino acids simultaneously. This observation strengthens the argument that the first peptides could have formed from specific, direct interactions between amino acids and RNA. The conclusion of this work is that small RNAs may have served important functions in the origin of translation during the RNA world. The formation of an ester bond between an amino acid and an RNA molecule can be catalyzed by RNA with very little sequence information. Moreover, I show that the RNA can interact specifically not just with individual amino acids, but also with multiple amino acids. This may provide an explanation for how the first coded peptides formed in the absence of protein catalysts.

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