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Cited by 10Origins and Evolution of LifeRNA and protein synthesis mechanismsDNA and Nucleic Acid Chemistry

Overcoming nucleotide bias in the nonenzymatic copying of RNA templates

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Duzdevich, Daniel, Carr, Christopher E, Colville, Ben W F, Aitken, Harry R M, Szostak, Jack W·2024·Nucleic Acids Research
DOI 10.1093/nar/gkae982PMC PMC11662926

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Abstract

The RNA World hypothesis posits that RNA was the molecule of both heredity and function during the emergence of life. This hypothesis implies that RNA templates can be copied, and ultimately replicated, without the catalytic aid of evolved enzymes. A major problem with nonenzymatic template-directed polymerization has been the very poor copying of sequences containing rA and rU. Here, we overcome that problem by using a prebiotically plausible mixture of RNA mononucleotides and random-sequence oligonucleotides, all activated by methyl isocyanide chemistry, that direct the uniform copying of arbitrary-sequence templates, including those harboring rA and rU. We further show that the use of this mixture in copying reactions suppresses copying errors while also generating a more uniform distribution of mismatches than observed for simpler systems. We find that oligonucleotide competition for template binding sites, oligonucleotide ligation and the template binding properties of reactant intermediates work together to reduce product sequence bias and errors. Finally, we show that iterative cycling of templated polymerization and activation chemistry improves the yields of random-sequence products. These results for random-sequence template copying are a significant advance in the pursuit of nonenzymatic RNA replication.

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  • Similar observations to the complementary 4-mer effect have been made by Szostak and co-workers studying 5′-5′imidazolium bridged dinucleotides.

    “It should also be noted that similar observations have been made by Szostak and co-workers studying 5′-5′imidazolium bridged dinucleotides.39”

    From Sequencing of <scp>d</scp>/<scp>l</scp>-DNA and XNA by Templated-Synthesis (2025) · cites this paper as [39]

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Authors
Duzdevich, D., Carr, C. E., Colville, B. W. F., Aitken, H. R. M., & Szostak, J. W.
Affiliations
  • University of Freiburg (DE)
  • Georgia Institute of Technology (US)
  • University of Chicago (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Duzdevich, Daniel
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2024-11-12
Volume
52
Issue
22
Pages
13515-13529
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkae982
PMC
PMC11662926
OpenAlex
W4404283078
Cited by
10
References
5
Citations by year
2026: 7 · 2025: 3
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
  • University of Chicago (cc-by)
Funders
  • Simons Foundation (290363)
  • National Science Foundation (2104708)
  • National Aeronautics and Space Administration (80NSSC22K0188)
  • Marie Skłodowska-Curie FRIAS COFUND Fellowship
  • Howard Hughes Medical Institute
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
RNA world, template polymerization, nucleotide bias, copying errors, mismatch distribution, template binding, prebiotic chemistry
MeSH terms
Nucleotides, Oligonucleotides, RNA, Templates, Genetic, Polymerization

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