A cross-chiral RNA polymerase ribozyme
Open accessAbstract
Thirty years ago it was shown that the non-enzymatic, template-directed polymerization of activated mononucleotides proceeds readily in a homochiral system, but is severely inhibited by the presence of the opposing enantiomer. This finding poses a severe challenge for the spontaneous emergence of RNA-based life, and has led to the suggestion that either RNA was preceded by some other genetic polymer that is not subject to chiral inhibition or chiral symmetry was broken through chemical processes before the origin of RNA-based life. Once an RNA enzyme arose that could catalyse the polymerization of RNA, it would have been possible to distinguish among the two enantiomers, enabling RNA replication and RNA-based evolution to occur. It is commonly thought that the earliest RNA polymerase and its substrates would have been of the same handedness, but this is not necessarily the case. Replicating D- and L-RNA molecules may have emerged together, based on the ability of structured RNAs of one handedness to catalyse the templated polymerization of activated mononucleotides of the opposite handedness. Here we develop such a cross-chiral RNA polymerase, using in vitro evolution starting from a population of random-sequence RNAs. The D-RNA enzyme, consisting of 83 nucleotides, catalyses the joining of L-mono- or oligonucleotide substrates on a complementary L-RNA template, and similar behaviour occurs for the L-enzyme with D-substrates and a D-template. Chiral inhibition is avoided because the 10(6)-fold rate acceleration of the enzyme only pertains to cross-chiral substrates. The enzyme's activity is sufficient to generate full-length copies of its enantiomer through the templated joining of 11 component oligonucleotides.
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The 16.12t D-RNA ribozyme exhibited sufficient activity to generate full-length copies of its enantiomer through the template-assisted ligation of 11 oligonucleotides.
“The 16.12t D-RNA ribozyme was eventually discovered which exhibited sufficient activity to generate full-length copies of its enantiomer through the template-assisted ligation of 11 oligonucleotides.”
From Possible chemical and physical scenarios towards biological homochirality (2022) · cites this paper as [589]
A RNA polymerase ribozyme can catalyze the templated synthesis of RNA oligomers of the opposite configuration.
“the possibility for a RNA polymerase ribozyme to catalyze the templated synthesis of RNA oligomers of the opposite configuration.”
From Possible chemical and physical scenarios towards biological homochirality (2022) · cites this paper as [589]
Various ribozymes have been shown to copy themselves either partially or entirely, but these reactions have always depended on carefully curated sets of preformed oligonucleotide substrates, restricting the ability of the copied RNA to mutate and evolve.
“Although various ribozymes have been shown to copy themselves either partially or entirely, these reactions have always depended on carefully curated sets of preformed oligonucleotide substrates, thereby restricting the ability of the copied RNA to mutate and evolve (15, 18, 28–30).”
From An RNA polymerase ribozyme that synthesizes its own ancestor (2020) · cites this paper as [30]
Known RNA polymerase ribozymes are not yet able to copy an arbitrary sequence due to obligatory base-pairing between enzyme and substrate.
“Although the known RNA polymerase ribozymes are not yet able to copy an arbitrary sequence due to obligatory base-pairing between enzyme and substrate”
From The RNA world as a model system to study the origin of life (2015) · cites this paper as [108]
A cross-chiral ligase system copies RNAs of the opposite handedness, and vice versa for its enantiomer, representing an unconventional pathway to RNA replication.
“a recent approach neatly sidesteps this problem using a ‘cross-chiral’ ligase; in this system, a ligase copies RNAs of the opposite handedness, and vice versa for its enantiomer [108].”
From The RNA world as a model system to study the origin of life (2015) · cites this paper as [108]
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Self-citation
- Authors
- Sczepanski, J. T., & Joyce, G. F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Joyce, Gerald F.
- Venue
- Nature
- Published
- 2014-10-29
- Volume
- 515
- Issue
- 7527
- Pages
- 440-442
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4239201
- OpenAlex
- W2130922853
- Cited by
- 186
- References
- 21
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 9 · 2023: 7 · 2022: 16 · 2021: 12 · 2020: 20 · 2019: 17 · 2018: 13 · 2017: 24 · 2016: 18 · 2015: 27 · 2014: 2
- FWCI
- 12.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of General Medical Sciences (F32GM101741)
- Topics
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- ribozymes, homochirality, origin of life, RNA world, chiral recognition, in vitro evolution, RNA replication
- MeSH terms
- Origin of Life, Base Sequence, Biopolymers, Kinetics, Molecular Sequence Data, Nucleic Acid Conformation, Oligonucleotides, RNA, DNA-Directed RNA Polymerases, Stereoisomerism, Templates, Genetic, RNA, Catalytic, Directed Molecular Evolution, Evolution, Chemical, Base Pairing, Biocatalysis, Polymerization
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