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RNA-catalysed nucleotide synthesis

Abstract

The ‘RNA world’ hypothesis proposes that early life developed by making use of RNA molecules, rather than proteins, to catalyse the synthesis of important biological molecules1. It is thought, however, that the nucleotides constituting RNA were scarce on early Earth1,2,3,4. RNA-based life must therefore have acquired the ability to synthesize RNA nucleotides from simpler and more readily available precursors, such as sugars and bases. Plausible prebiotic synthesis routes have been proposed for sugars5, sugar phosphates6 and the four RNA bases7,8,9,10,11, but the coupling of these molecules into nucleotides, specifically pyrimidine nucleotides, poses a challenge to the RNA world hypothesis1,2,3. Here we report the application of in vitro selection to isolate RNA molecules that catalyse the synthesis of a pyrimidine nucleotide at their 3′ terminus. The finding that RNA can catalyse this type of reaction, which is modelled after pyrimidine synthesis in contemporary metabolism, supports the idea of an RNA world that included nucleotide synthesis and other metabolic pathways mediated by ribozymes.

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Figure 1
Figure 2: In vitro selection scheme.
Figure 3: Increased ribozyme activity with successive rounds of selection.
Figure 4: Analysis of ribozyme sequences and their catalytic proficiencies.
Figure 5: Two-dimensional TLC analysis18 of ribozyme-synthesized 4SU after labelling and diges.

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Acknowledgements

We thank J. Stubbe, P. Zamore and members of the lab for helpful comments on the manuscript, and G. Joyce for providing the sequence of the RNA-cleaving DNA enzyme28 before publication. This work was supported by an MRC (Canada) postdoctoral fellowship to P.J.U. and a grant from the Searle Scholars Program/The Chicago Community Trust to D.P.B.

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Unrau, P., Bartel, D. RNA-catalysed nucleotide synthesis. Nature 395, 260–263 (1998). https://doi.org/10.1038/26193

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