The RNA World Hypothesis suggests that early in the development of life, RNA played a crucial role in both storing genetic information and performing essential functions, long before DNA and proteins took over these roles. This idea rests on the assumption that RNA molecules could copy themselves without needing complex enzymes to assist the process. However, one of the major challenges has been getting RNA sequences containing two important components, adenine (rA) and uracil (rU), to copy themselves efficiently.
In a recent study, researchers at the University of Chicago tackled this issue by developing a method that mimics how RNA might have replicated billions of years ago. They used a mixture of RNA building blocks (mononucleotides) and short RNA fragments (oligonucleotides) to act as templates. All of these components were activated by a chemical called methyl isocyanide, which could have been available in early Earth conditions. This new approach allowed the researchers to successfully copy RNA sequences that contain rA and rU, overcoming a significant barrier in the field.
Templated nonenzymatic polymerization, activation chemistry, and sequencing of products
A. Mechanism of templated polymerization by imidazole-activated 5′-5′ bridged dinucleotide that can bind a primer-template junction. B. Direct extension via the activated mononucleotide. C. A downstream oligonucleotide can sandwich any reactive species against the primer. D. A mononucleotide can form a 5′-5′ bridged species with an oligonucleotide. E. Direct ligation of an activated oligonucleotide, analogous to mechanism (B). F. Ligation via a sterically displaced 5′ bridged mononucleotide. G. Many species compete for binding sites in a heterogeneous reaction. H. A mixture of mono- and oligonucleotides can be activated in situ by MeNC-mediated chemistry. I. (Adapted from 1.) A self-priming hairpin with a random-sequence template captures the products of polymerization. Sequencing analysis then reveals the ensemble of template-specific products.
Not only did this method improve copying accuracy, but it also reduced the number of errors made during the process. The system achieved this by using competition among oligonucleotides to bind to the template, which helped ensure that the correct sequences were copied with fewer mistakes. The researchers also observed that repeating the activation and copying steps several times increased the amount of copied RNA produced.
This breakthrough brings scientists closer to understanding how RNA could have replicated on its own in the early stages of life’s development. By showing that random RNA sequences can be copied accurately without enzymes, this study provides valuable insight into how life might have first emerged through simple molecular processes.