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Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation

Nature Chemistry volume 5, pages 383–389 (2013)Cite this article

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Abstract

The recent synthesis of pyrimidine ribonucleoside-2′,3′-cyclic phosphates under prebiotically plausible conditions has strengthened the case for the involvement of ribonucleic acid (RNA) at an early stage in the origin of life. However, a prebiotic conversion of these weakly activated monomers, and their purine counterparts, to the 3′,5′-linked RNA polymers of extant biochemistry has been lacking (previous attempts led only to short oligomers with mixed linkages). Here we show that the 2′-hydroxyl group of oligoribonucleotide-3′-phosphates can be chemoselectively acetylated in water under prebiotically credible conditions, which allows rapid and efficient template-directed ligation. The 2′-O-acetyl group at the ligation junction of the product RNA strand can be removed under conditions that leave the internucleotide bonds intact. Remarkably, acetylation of mixed oligomers that possess either 2′- or 3′-terminal phosphates is selective for the 2′-hydroxyl group of the latter. This newly discovered chemistry thus suggests a prebiotic route from ribonucleoside-2′,3′-cyclic phosphates to predominantly 3′,5′-linked RNA via partially 2′-O-acetylated RNA.

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Figure 1: Chemoselective acetylation of RNA.
Figure 2: Chemoselective acetylation: mixtures and alternative electrophiles.
Figure 3: Chemoselective acetylation of 3′P-oligoribonucleotides expedites templated ligation.
Figure 4: Quantification of ligation products.
Figure 5: Chemoselective acetylation favours ligation of 3′P oligomers over 2′P oligomers.
Figure 6: Templated ligation of acetylated 3′P and 2′P oligomers affords 3′,5′- and 2′,5′-linkages, respectively.

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Acknowledgements

This work was funded by the Engineering and Physical Sciences Research Council through the provision of postdoctoral fellowships (C.D.D. and B.G.) and PhD studentships (M.W.P., S.I. and C.K.W.C.), the Medical Research Council through the provision of career development fellowships (F.R.B. and J.X., project no. MC_UP_A024_1009) and the Origin of Life Challenge, for which we thank H. Lonsdale. We thank C. Hilcenko, M. J. Churcher and V. B. Pinheiro for advice on polyacrylamide gel electrophoresis and fluorescence scanning, and D. Williams for advice on solid-phase oligonucleotide synthesis.

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Author notes

  1. Béatrice Gerland, Saidul Islam & Matthew W. Powner

    Present address: Present addresses: Faculté de chimie, Université de Strasbourg, 1 rue Blaise Pascal, 67008 Strasbourg Cedex, France (B.G.); School of Biological and Chemical Sciences, Joseph Priestley Building, Queen Mary University London, Mile End Road, London E1 4NS, UK (S.I.); Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H 0AJ, UK (M.W.P.),

Authors and Affiliations

  1. Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK

    Frank R. Bowler, Christopher K. W. Chan, Colm D. Duffy, John D. Sutherland & Jianfeng Xu

  2. School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK

    Béatrice Gerland, Saidul Islam, Matthew W. Powner & John D. Sutherland

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Contributions

F.R.B., C.K.W.C., C.D.D., B.G., S.I., M.W.P., J.D.S. and J.X. conceived and designed the experiments and analysed the data. F.R.B., C.K.W.C., C.D.D., B.G., S.I., M.W.P. and J.X. performed the experiments. F.R.B., S.I., M.W.P. and J.D.S. co-wrote the paper.

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Correspondence to John D. Sutherland.

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Bowler, F., Chan, C., Duffy, C. et al. Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation. Nature Chem 5, 383–389 (2013). https://doi.org/10.1038/nchem.1626

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