EAGER: Exploring the RNA World and the RNA-peptide world hypothesis using a novel Dynamic Combinatorial Chemistry (DCC) system

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The universal biomolecule RNA possesses dual abilities to serve as a repository for genetic information and to catalyze reactions. These properties make RNA unique and different from the other two biomolecules, DNA and proteins, which led to the idea that an early ‘RNA World’ may have existed. An alternate hypothesis is rapidly gaining traction – that RNA and peptides both contributed to early molecular evolution by mutually supporting each other. Understanding the potential events that might have occurred in an ‘RNA World’, or ‘RNA-Peptide’ world, is important to understand the origins and early history of life. A novel Dynamic Combinatorial Chemistry (DCC) system will be employed to address how RNAs recombine when subjected to cycles of cleavage and ligation under laboratory conditions. The work will be carried out at the University of Houston, a minority serving institution. Undergraduate students will be trained during the course of the project and have the opportunity to co-author publications. Additionally, the project will support public education and outreach on topics related to the origin and early history of living systems.In the DCC system, one enzyme (benzonase) cleaves RNAs, resulting in products with a 3’ hydroxyl and 5’ phosphate, which are then ligated by another enzyme (T4 RNA ligase). This system will be employed to evaluate the competing RNA world and RNA-peptide world theories. If a dynamically changing population of small RNAs continues to change independently in the absence of amino acids/peptides, it would support existence of an extended RNA World. If instead, the presence of peptides and/or amino acids significantly impacts the RNA sequence diversity, it would suggest a rapid transition to an RNA-Peptide World could have occurred. The findings will advance understanding of the role of RNA (and peptides/amino acids) in the origins of life besides providing a novel and unique approach to exploring RNA sequence space. For example, such a system applied to sequences from RNA viruses could shed light on the dynamics of RNA genome recombination.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.