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An RNA polymerase ribozyme that synthesizes its own ancestor
Edited by Jack W. Szostak, Massachusetts General Hospital, Boston, MA, and approved December 28, 2019 (received for review August 16, 2019)

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Significance
Life depends on the propagation of heritable information across successive generations. An RNA polymerase ribozyme was obtained by in vitro evolution that has an unprecedented level of activity in copying complex RNA templates. The polymerase is able to synthesize its own evolutionary ancestor, an RNA ligase ribozyme, in the form of three fragments that assemble to give a functional complex, as well as to synthesize the complements of each of those three fragments. However, when pushed to the limits of its activity, the polymerase operates with lower fidelity, which is an impediment to maintaining functional information, as would be needed to provide an RNA-based living system.
Abstract
The RNA-based organisms from which modern life is thought to have descended would have depended on an RNA polymerase ribozyme to copy functional RNA molecules, including copying the polymerase itself. Such a polymerase must have been capable of copying structured RNAs with high efficiency and high fidelity to maintain genetic information across successive generations. Here the class I RNA polymerase ribozyme was evolved in vitro for the ability to synthesize functional ribozymes, resulting in the markedly improved ability to synthesize complex RNAs using nucleoside 5′-triphosphate (NTP) substrates. The polymerase is descended from the class I ligase, which contains the same catalytic core as the polymerase. The class I ligase can be synthesized by the improved polymerase as three separate RNA strands that assemble to form a functional ligase. The polymerase also can synthesize the complement of each of these three strands. Despite this remarkable level of activity, only a very small fraction of the assembled ligases retain catalytic activity due to the presence of disabling mutations. Thus, the fidelity of RNA polymerization should be considered a major impediment to the construction of a self-sustained, RNA-based evolving system. The propagation of heritable information requires both efficient and accurate synthesis of genetic molecules, a requirement relevant to both laboratory systems and the early history of life on Earth.
Footnotes
↵1Present address: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
- ↵2To whom correspondence may be addressed. Email: dhorning{at}salk.edu or gjoyce{at}salk.edu.
Author contributions: K.F.T., D.P.H., and G.F.J. designed research; K.F.T. and D.P.H. performed research; K.F.T., M.N.S., D.P.H., and G.F.J. analyzed data; and K.F.T., D.P.H., and G.F.J. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Data deposition: Sequencing data and corresponding fidelity measurements reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE142114).
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1914282117/-/DCSupplemental.
Published under the PNAS license.
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