Efficient and Rapid Template-Directed Nucleic Acid Copying Using 2′-Amino-2′,3′-dideoxyribonucleoside−5′-Phosphorimidazolide Monomers
Open accessAbstract
The development of a sequence-general nucleic acid copying system is an essential step in the assembly of a synthetic protocell, an autonomously replicating spatially localized chemical system capable of spontaneous Darwinian evolution. Previously described nonenzymatic template-copying experiments have validated the concept of nonenzymatic replication, but have not yet achieved robust, sequence-general polynucleotide replication. The 5'-phosphorimidazolides of the 2'-amino-2',3'-dideoxyribonucleotides are attractive as potential monomers for such a system because they polymerize by forming 2'-->5' linkages, which are favored in nonenzymatic polymerization reactions using similarly activated ribonucleotides on RNA templates. Furthermore, the 5'-activated 2'-amino nucleotides do not cyclize. We recently described the rapid and efficient nonenzymatic copying of a DNA homopolymer template (dC(15)) encapsulated within fatty acid vesicles using 2'-amino-2',3'-dideoxyguanosine-5'-phosphorimidazolide as the activated monomer. However, to realize a true Darwinian system, the template-copying chemistry must be able to copy most sequences and their complements to allow for the transmission of information from generation to generation. Here, we describe the copying of a series of nucleic acid templates using 2'-amino-2',3'-dideoxynucleotide-5'-phosphorimidazolides. Polymerization reactions proceed rapidly to completion on short homopolymer RNA and LNA templates, which favor an A-type duplex geometry. We show that more efficiently copied sequences are generated by replacing the adenine nucleobase with diaminopurine, and uracil with C5-(1-propynyl)uracil. Finally, we explore the copying of longer, mixed-sequence RNA templates to assess the sequence-general copying ability of 2'-amino-2',3'-dideoxynucleoside-5'-phosphorimidazolides. Our results are a significant step forward in the realization of a self-replicating genetic polymer compatible with protocell template copying and suggest that N2'-->P5'-phosphoramidate DNA may have the potential to function as a self-replicating system.
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Similar non-enzymatic polymerization systems have been used to demonstrate replication in model protocells.
“Similar systems have been previously used to demonstrate replication in model protocells (25,26).”
From The prebiotic evolutionary advantage of transferring genetic information from RNA to DNA (2011) · cites this paper as [25]
Polymerization of 2'-amino 5'-phosphorimidazolide monomers was faster on LNA templates than on RNA templates, which were in turn better than DNA or 2'-5' linked DNA templates.
“The polymerization of 2 ' -amino 5 ' -phosphorimidazolide monomers was, for example, faster on LNA templates than on RNA templates, which were in turn better than DNA or 2 ' -5 ' linked DNA templates.”
From The eightfold path to non-enzymatic RNA replication (2012) · cites this paper as [47]
In a comparison of primer-extension reactions on different templates, the best templates were those more conformationally constrained toward a canonical A-type helix with 3'-endo monomer units.
“In a comparison of primer-extension reactions on a series of different templates, the best templates were those that were more conformationally constrained in the direction of a canonical A-type helix with 3 ' -endo monomer units [47].”
From The eightfold path to non-enzymatic RNA replication (2012) · cites this paper as [47]
Nonenzymatic polymerization is most effective in the context of an A-form helix.
“Nonenzymatic polymerization is most effective in the context of an A-form helix.13”
From Replacing Uridine with 2-Thiouridine Enhances the Rate and Fidelity of Nonenzymatic RNA Primer Extension (2015) · cites this paper as [13]
G:U and A:C wobble pairing lead to a very high error rate in nonenzymatic template copying.
“A second major problem is that G:U and A:C wobble pairing lead to a very high error rate in nonenzymatic template copying,13 potentially precluding the emergence of functional RNAs such as ribozymes from diverse sequence populations.”
From Replacing Uridine with 2-Thiouridine Enhances the Rate and Fidelity of Nonenzymatic RNA Primer Extension (2015) · cites this paper as [13]
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Self-citation
- Authors
- Schrum, J. P., Ricardo, A., Krishnamurthy, M., Blain, J. C., & Szostak, J. W.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Szostak, Jack W.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-09-16
- Volume
- 131
- Issue
- 40
- Pages
- 14560-14570
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC2759813
- OpenAlex
- W2056152537
- Cited by
- 103
- References
- 53
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 4 · 2016: 6 · 2015: 9 · 2014: 12 · 2013: 8 · 2012: 13
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 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
- protocells, RNA template, fatty acid vesicles, Darwinian evolution
- MeSH terms
- DNA, Imidazoles, Nucleic Acids, RNA, Templates, Genetic, Dideoxynucleosides, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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