The eightfold path to non-enzymatic RNA replication

Jack W Szostak

doi:10.1186/1759-2208-3-2

Abstract

The first RNA World models were based on the concept of an RNA replicase - a ribozyme that was a good enough RNA polymerase that it could catalyze its own replication. Although several RNA polymerase ribozymes have been evolved in vitro, the creation of a true replicase remains a great experimental challenge. At first glance the alternative, in which RNA replication is driven purely by chemical and physical processes, seems even more challenging, given that so many unsolved problems appear to stand in the way of repeated cycles of non-enzymatic RNA replication. Nevertheless the idea of non-enzymatic RNA replication is attractive, because it implies that the first heritable functional RNA need not have improved replication, but could have been a metabolic ribozyme or structural RNA that conferred any function that enhanced protocell reproduction or survival. In this review, I discuss recent findings that suggest that chemically driven RNA replication may not be completely impossible.

Highlights

Considerable evidence supports the RNA World hypothesis of an early phase of life, prior to the evolution of coded protein synthesis, in which cellular biochemistry and genetics were largely the province of RNA
The central question concerning the origin of life has become: how did the RNA World emerge from the prebiotic chemistry of the early earth? The emergence of the RNA World can be divided, conceptually, into two phases: first, the prebiotic synthesis of ribonucleotides and of RNA molecules, and second, the replication of genomic RNA molecules within replicating protocells
As recently as 2004, Leslie Orgel, one of the great founding fathers of the field of prebiotic chemistry, suggested that “the abiotic synthesis of RNA is so difficult that it is unclear that the RNA World could have evolved de novo on the primitive earth” [3]

Summary

Introduction

Even given prebiotically generated RNA templates and abundant ribonucleotides, we do not understand how cycles of template-directed RNA replication could occur. Protocellular structure poses more problems initially, it is simpler to solve these problems up front rather than leave them till later when they could become completely intractable In this Perspective, I will focus on RNA replication in the context of a cellular environment, as described in recent model studies [9,10]. In one of the most impressive examples of such chemistry, a full length complement of a 14-mer all GC template was generated in the presence of activated G and C monomers, albeit in low yield (< 2%) [14] Despite such achievements, the efficient and accurate copying of arbitrary template sequences has remained frustratingly out of reach. I will discuss the implications of chemical RNA replication for the emergence of the RNA World from the prebiotic chemistry of the early earth

Discussion

Conclusions

Joyce GF

50. Gilham PT

63. Miller SL