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Cited by 152DNA and Nucleic Acid ChemistryRNA and protein synthesis mechanismsDNA Repair Mechanisms

Dynamic basis for dG•dT misincorporation via tautomerization and ionization

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Kimsey, Isaac J., Szymanski, Eric S., Zahurancik, Walter J., Shakya, Anisha, Xue, Yi, Chu, Chia-Chieh, Sathyamoorthy, Bharathwaj, Suo, Zucai +1 more·2018·Nature
DOI 10.1038/nature25487PMC PMC5808992
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Abstract

Tautomeric and anionic Watson-Crick-like mismatches have important roles in replication and translation errors through mechanisms that are not fully understood. Here, using NMR relaxation dispersion, we resolve a sequence-dependent kinetic network connecting G•T/U wobbles with three distinct Watson-Crick mismatches: two rapidly exchanging tautomeric species (G enol•T/UG•T enol/U enol; population less than 0.4%) and one anionic species (G•T-/U-; population around 0.001% at neutral pH). The sequence-dependent tautomerization or ionization step was inserted into a minimal kinetic mechanism for correct incorporation during replication after the initial binding of the nucleotide, leading to accurate predictions of the probability of dG•dT misincorporation across different polymerases and pH conditions and for a chemically modified nucleotide, and providing mechanisms for sequence-dependent misincorporation. Our results indicate that the energetic penalty for tautomerization and/or ionization accounts for an approximately 10-2 to 10-3-fold discrimination against misincorporation, which proceeds primarily via tautomeric dG enol•dT and dG•dT enol, with contributions from anionic dG•dT- dominant at pH 8.4 and above or for some mutagenic nucleotides.

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  • Tautomerisation in DNA has been experimentally observed using NMR relaxation dispersion, where hairpin DNA duplex structures were observed to interchange between a wobble G-T and a Watson-Crick-like structure via tautomerisation or ionisation.

    “More recently, tautomerisation in DNA has been experimentally observed using NMR relaxation dispersion.Here, hairpin DNA duplex structures were observed to interchange between a wobble G-T and a Watson-Crick-like structure via tautomerisation (neutral) or ionisation (charged) 9,51 .”

    From An open quantum systems approach to proton tunnelling in DNA (2022) · cites this paper as [9]

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Cited by

Sorted by citations

Authors
Kimsey, I. J., Szymanski, E. S., Zahurancik, W. J., Shakya, A., Xue, Y., Chu, C.-C., Sathyamoorthy, B., Suo, Z., & Al-Hashimi, H. M.
Affiliations
  • Duke Medical Center (US)
  • The Ohio State University (US)
  • University of Michigan (US)
Corresponding author
Suo, Zucai
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2018-01-31
Volume
554
Issue
7691
Pages
195-201
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature25487
PMC
PMC5808992
OpenAlex
W2786442837
Cited by
152
References
2
Citations by year
2026: 13 · 2025: 13 · 2024: 13 · 2023: 19 · 2022: 22 · 2021: 23 · 2020: 14 · 2019: 17 · 2018: 18
FWCI
6.40
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Science Foundation
  • Ohio State University
  • Pelotonia
  • National Institutes of Health
  • National Institute of General Medical Sciences (P01GM066275, P50GM103297, R01GM089846)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
tautomerism, ionization, DNA polymerase, kinetic model, mutagenesis, NMR relaxation dispersion, chemically modified nucleotides, pH dependence, replication errors
MeSH terms
Animals, Anions, DNA, DNA-Directed DNA Polymerase, DNA Replication, Guanine, Humans, Hydrogen-Ion Concentration, Kinetics, Magnetic Resonance Spectroscopy, Probability, Thymine, Mutagenesis, Base Pair Mismatch, Rats

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