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An RNA polymerase ribozyme that synthesizes its own ancestor

Tjhung, Katrina and Shokhirev, Maxim N. and Horning, David P. and Joyce, Gerald F. (2020) An RNA polymerase ribozyme that synthesizes its own ancestor. Proceedings of the National Academy of Sciences. ISSN 0027-84241091-6490

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.

Item Type: Article
Keywords: directed evolution RNA enzyme RNA replication
Date Deposited: 15 Feb 2020 00:45
Last Modified: 15 Feb 2020 00:45
URI: https://oak.novartis.com/id/eprint/40711

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