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Dynamic basis for dG•dT misincorporation via tautomerization and ionization

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 (Genol•T/UG•Tenol/Uenol; 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 dGenol•dT and dG•dTenol, with contributions from anionic dG•dT dominant at pH 8.4 and above or for some mutagenic nucleotides.

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Figure 1: Tilting the rapid tautomeric equilibria in excited-state WC-like mismatches.
Figure 2: Resolving rapidly interconverting tautomers.
Figure 3: Three-state exchange with triangular topology and minor exchange between tautomeric and anionic WC-like excited states.
Figure 4: Kinetic mechanism of dG•dT misincorporation.
Figure 5: Measured versus predicted misincorporation probabilities and rates.

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Acknowledgements

We thank members of the Al-Hashimi laboratory and T. Oas for discussions and input. We acknowledge technical support and resources from the Duke Magnetic Resonance Spectroscopy Center and the Duke Shared Cluster Resource. This work was supported by grants from the National Institutes of Health (NIH R01GM089846, P01GM0066275 and P50GM103297) and an Agilent Thought Leader Award to H.M.A., and a grant from the National Science Foundation (MCB-1716168) to Z.S. W.J.Z. was supported by a Pelotonia Graduate Fellowship from The Ohio State University Comprehensive Cancer Center.

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Contributions

I.J.K., E.S.S., and H.M.A. conceived the NMR research and kinetic model. W.J.Z. and Z.S. conceived the kinetic experiments. I.J.K., E.S.S., W.J.Z., Z.S. and H.M.A. wrote the manuscript. I.J.K. synthesized all DNA constructs as well as the RNA hpUG-CGC, hpUG-CGU, and xptG riboswitch constructs, and collected and analysed all NMR relaxation dispersion data. E.S.S. and H.M.A. constructed and tested the kinetic models of misincorporation with input from Z.S. W.J.Z. performed all kinetic experiments and provided input on the kinetic model and simulations with help from Z.S. A.S. synthesized A20G and A22G HIV-I TAR constructs. Y.X. synthesized and assigned p5abc and glnA riboswitch constructs. C.-C.C. synthesized and assigned the HIV-I RRE construct. B.S. synthesized and assigned the HIV-I SL1 dimer complex.

Corresponding authors

Correspondence to Zucai Suo or Hashim M. Al-Hashimi.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks J. Essigmann, M. Goodman and E. Westhof for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Watson–Crick-like mismatches.

a, Watson–Crick-like mismatches stabilized by tautomeric and ionic base forms.

Extended Data Figure 2 DNA and RNA constructs used in this study.

a, Secondary structures of the various DNA and RNA constructs used in this study. G•T/U mismatches that show signs of chemical exchange directed towards tautomeric and/or anionic WC-like mismatches are highlighted in blue and green, respectively. G•T/U mismatches that show no evidence for WC-like relaxation dispersion are highlighted in brown. The value of Kt measured at near-neutral pH is shown next to each mismatch. The DickersonTG-CGA, hpTG-CGC and hpUG-CGC sequences contexts were studied in a previous publication8. b, 2D [15N, 1H] HSQC spectra of DNA and RNA constructs used in this study showing the imino resonances of G-N1/H1 and T/U-N3/H3 targeted for relaxation dispersion measurements. The spectrum shown for xptG was collected at pH 6.7 and 25 °C in potassium acetate buffer as described previously8.

Extended Data Figure 3 Relaxation dispersion profiles measured in DNA and RNA at near-neutral pH.

a, 15N G-N1 and T/U-N3 relaxation dispersion measured for G•T/U mismatches at pH 6.4–6.9 and 10–25 °C showing wobble  tautomer exchange. Note that in addition to wobble tautomer exchange, tp5abc undergoes an independent, slower exchange process involving a change in secondary structure that is described in detail elsewhere50. The trend lines represent B–M two- or three-state fits. Constructs containing a chemically modified base are indicated by . b, The absence of 15N relaxation dispersion for rG•rU mismatches near bulges, apical loops or three-way junctions. Error bars reflect experimental uncertainty (one s.d., see Supplementary Methods). c, No correlation is observed between ground state (GS) wobble G-N1 and T/U-N3 chemical shifts for DNA (n = 5) or RNA (n = 8). Error bars in a and b reflect experimental uncertainty (one s.d., see Supplementary Methods).

Extended Data Figure 4 Establishing lower limits for the rates of base pair tautomeric exchange.

Agreement between measured and predicted R values (scaled weight, equation (2) in Supplementary Methods) when varying the exchanges rates of wobble G•Tenol/Uenol () and G•Tenol/UenolGenol•T/U (kt). See Supplementary Methods for additional details.

Extended Data Figure 5 Relaxation dispersion profiles measured in DNA and RNA at high pH.

a, b, B–M three-state fits of RNA (a) and DNA (b) 15N relaxation dispersion data for starlike and triangular topologies (as indicated within the plots). The relative statistical weights wAIC and wBIC (refs 51, 52) for each fit were used to select the model (representative starlike versus triangular, comparisons with linear models shown in Supplementary Table 6). Error bars reflect experimental uncertainty (one s.d., see Supplementary Methods).

Extended Data Figure 6 Discerning minor exchange between WC-like tautomeric and anionic G•T/U mismatches

a, Topologies used to model chemical exchange. Individual rate constants are shown for each process of the different topologies. b, Left, B–M simulations showing that when R2(GS) ≠ R2(ES1) and R2(GS) ≠ R2(ES2), no apparent peak asymmetry is observed. Right, B–M simulations showing that minor exchange between two ESs in a triangular topology induces asymmetry in the relaxation dispersion profiles and opposite changes in the apparent chemical shift for the two ESs. c, B–M simulations (solid lines) showing the fitted exchange parameters for hpUG-CGC at pH 8.4 and 10 °C (Supplementary Table 5) when including minor exchange in a triangular topology. For comparison, simulations using the same parameters without minor exchange (kES1→ES2 = 0 and kES2→ES1 = 0) are also shown (dashed lines). d, Dashed lines denote three-state B–M best fit to starlike topology (kES1 → ES2 = 0 and kES2 → ES1 = 0) to data simulated with triangular topology with minor exchange (solid lines). Shown to the right is the over- or underestimation of the true (green) versus fitted (red) ES chemical shifts when fitting relaxation dispersion profiles that have triangular topology with minor exchange to a starlike model that has no minor exchange. e, The ES1 〈∆ωrG-N1〉 and 〈∆ωrU-N3〉 values as a function of pH derived from the three-state B–M fit with triangular and starlike topology. f, Forward (kES1 → ES2) and reverse (kES2 → ES1) minor exchange rate constants for hpTG-GGC (pH 8 and 8.4) and hpUG-CGC (pH 7.9 and 8.4) as a function of temperature. Error bars in e and f reflect experimental uncertainty (one s.d., Supplementary Methods).

Extended Data Figure 7 Kinetic mechanisms used to model misincorporation.

Rate constants for each step are listed in Supplementary Table 7.

Extended Data Figure 8 Benchmarking kinetic simulations of misincorporation.

a, Comparison of kpol and Kd values for correct incorporation measured experimentally for human DNA polymerase ε with values computed on the basis of pre-steady state simulations using the microscopic rate constants provided in ref. 39. Error bars reflect fitting uncertainty as previously published39. b, Robustness of calculated kpol values for human DNA polymerase ε upon varying the rate constants (forward, blue; reverse, orange) for steps other than tautomerization or ionization by twofold (n = 200 independent simulations in which rate constants were varied randomly by up to twofold). As expected, the only rate constant with a substantial effect on the reported kpol values was the rate-limiting conformational change step k2 (middle).

Extended Data Figure 9 kobs values measured for human DNA polymerase β insertion.

Incorporation of dCTP (dCTP•dG) is shown on the left, that of dTTP (dTTP•dG) on the right. pH 8.4, 25 °C, 100 μM dNTP. DNA template sequence (5′ to 3′) is read from bottom (n + 1 position) to top (n − 1 position). Individual replicates (n = 3 independent experiments) are indicated by grey circles. Bar height reflects average of replicates, and error bars reflect one s.d.

Extended Data Figure 10 Fpol is primarily governed by ES1 populations.

Simulated Fpol values as a function of scaling up or scaling down of the kinetic exchange rate for ES1 formation (kex = kGS → ES1 + kES1 → GS) without altering the ES1 population. Increasing kex beyond values measured experimentally in this study (green dotted line) minimally affects Fpol; decreasing the kex within the range measured experimentally in this study (purple dotted line) also affects the value of Fpol only minimally. Much larger decreases in kex are required to significantly reduce the value of Fpol. 

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Kimsey, I., Szymanski, E., Zahurancik, W. et al. Dynamic basis for dG•dT misincorporation via tautomerization and ionization. Nature 554, 195–201 (2018). https://doi.org/10.1038/nature25487

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