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Trinucleotide substrates under pH–freeze–thaw cycles enable open-ended exponential RNA replication by a polymerase ribozyme

Attwater, James; Holliger, Philipp; Ohlendorf, Luis; Kwok, Samantha LY; Augustin, Teresa L; Curran, Joseph F; Gianni, Edoardo; (2025) Trinucleotide substrates under pH–freeze–thaw cycles enable open-ended exponential RNA replication by a polymerase ribozyme. Nature Chemistry 10.1038/s41557-025-01830-y. (In press). Green open access

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Abstract

RNA replication is considered a key process in the origins of life. However, both enzymatic and non-enzymatic RNA replication cycles are impeded by the ‘strand separation problem’, a form of product inhibition arising from the extraordinary stability of RNA duplexes and their rapid reannealing kinetics. Here we show that RNA trinucleotide triphosphates can overcome this problem by binding to and kinetically trapping dissociated RNA strands in a single-stranded form, while simultaneously serving as substrates for replication by an RNA polymerase ribozyme. When combined with coupled pH and freeze–thaw cycles, this enabled exponential replication of both (+) and (−) strands of double-stranded RNAs, including a fragment of the ribozyme itself. Subjecting random RNA sequence pools to open-ended replication yielded either defined replicating RNA sequences or the gradual emergence of diverse sequence pools. The latter derived from partial ribozyme self-replication alongside generation of new RNA sequences, and their composition drifted towards hypothesized primordial codons. These results unlock broader opportunities to model primordial RNA replication.

Type: Article
Title: Trinucleotide substrates under pH–freeze–thaw cycles enable open-ended exponential RNA replication by a polymerase ribozyme
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41557-025-01830-y
Publisher version: https://doi.org/10.1038/s41557-025-01830-y
Language: English
Additional information: © The Author(s), 2025. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Keywords: Chemical origin of life, RNA
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10209177
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