RNA is ubiquitous in biology today, from its role as a primer in DNA replication to its multiple roles in protein synthesis and its even more diverse roles in regulation. Most of the viruses that continue to plague us to this day are RNA viruses, while it is RNA based vaccines that provided the first and best weapons to fight these plagues. But why RNA? Why are we immersed in the biology of RNA? The answer lies in the early history of life, and its origins in the chemistry that led to RNA as the first biopolymer of life.
Why did life begin with RNA, and not DNA, or TNA, or ANA, or any of the myriad other nucleic acids (collectively referred to as XNAs) that look as if they could transmit genetic information and fold up into aptamers and catalysts? Part of the answer comes from the recent advances in prebiotic chemistry that describe plausible pathways for the synthesis of ribonucleotides on the early earth. However, many noncanonical nucleotides would have been generated together with ribonucleotides in ratios depending on the environmental conditions. If these noncanonical nucleotides were present with ribonucleotides in some prebiotic pool, and exposed to activating chemistry, their oligomerization would have led to a highly heterogeneous collection of oligonucleotides containing different types of nucleotides. To add to the complexity, these nucleotides could have been connected by a variety of different types of backbone linkages. How could anything resembling modern RNA, with a relatively homogeneous composition, have possibly emerged from this primordial heterogeneity? It now appears that the chemistry of nonenzymatic template copying would have strongly enriched for RNA over the course of multiple cycles of replication.
Jack’s laboratory has studied the chemistry of template copying using a simple model system in which an RNA primer bound to an RNA template is extended by reaction with activated ribonucleotides. In order to understand whether this copying chemistry would still work under more realistic conditions, we began to study the kinetics of copying using nonstandard nucleotides either as activated monomers, or when incorporated into the primer and template oligonucleotides. What we found surprised us: in all of the cases we have examined so far, chemical copying with ribonucleotides is faster than copying with alternative nucleotides. Furthermore, nonstandard nucleotides or backbone linkages in the template are readily copied into native RNA with ribonucleotides. Our results suggest that nonenzymatic copying served as a chemical selection mechanism that allowed relatively homogeneous RNA to emerge from a complex mixture of prebiotically synthesized nucleotides and oligonucleotides. The resulting RNA oligonucleotides could then have served as the genetic raw material for the emergence of the first RNA based protocells.
Professor of Chemistry and Chemical Biology and Genetics at Harvard University, an Investigator of the Howard Hughes Medical Institute, and the Alex Rich Distinguished Investigator at Massachusetts General HospitalView Slides
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