Base-pair Opening Dynamics of Nucleic Acids in Relation to Their Biological Function

Choi, Seo-Ree; Kim, Nahyun; Jin, Ho-Seong; Seo, Young-Jun; Lee, Juhyun; Lee, Joon‐Hwa

doi:10.1016/j.csbj.2019.06.008

Cited by 15 publications

(11 citation statements)

References 106 publications

(172 reference statements)

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“…Such dynamic processes are expected to be absent in undamaged, non-mismatched DNA helices which are not in-teracting with a reader protein or enzyme. 30,31 Collectively, our findings reveal that 5caC's pH-induced chameleonic behavior is not due to any permanent structural changes, opposite to previously reported results. 22,23 In fact, we observed that the repercussions of 5caC and 5fC incorporation into otherwise canonical dsDNA are uniquely perceptible in the context of conformational dynamics affecting at least two distinct timescales: a slower one (tens of milliseconds) and a faster one (hundreds of microseconds).…”

Section: Introductioncontrasting

confidence: 98%

¹H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives

Dubini

Korytiaková

Schinkel

et al. 2021

Preprint

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5-carboxycytosine (5caC) is a rare epigenetic modification found in nucleic acids of all domains of life. Despite its sparse genomic abundance, 5caC is presumed to play essential regulatory roles in transcription, maintenance and base-excision processes in DNA. In this work, we utilize nuclear magnetic resonance (NMR) spectroscopy to address the effects of 5caC incorporation into canonical DNA strands at multiple pH and temperature conditions. Our results demonstrate that 5caC has a pH-dependent global destabilizing and a base-pair mobility enhancing local impact on dsDNA, albeit without any detectable influence on the ground-state B-DNA structure. Measurement of hybridization thermodynamics and kinetics of 5caC-bearing DNA duplexes highlighted how acidic environment (pH 5.8 and 4.7) destabilizes the double-stranded structure by ≈10-20 kJ mol-1 at 37 °C when compared to the same sample at neutral pH. Protonation of 5caC results in a lower activation energy for the dissociation process and a higher barrier for annealing. Studies on conformational exchange on the µs time scale regime revealed a sharply localized base-pair motion involving exclusively the modified site and its immediate surroundings. By direct comparison with canonical and 5-formylcytosine (5fC)-edited strands, we were able to address the impact of the two most oxidized naturally occurring cytosine derivatives in the genome. These insights on 5caC's subtle sensitivity to acidic pH contribute to the long standing questions of its capacity as a substrate in base excision repair processes and its purpose as an independent, stable epigenetic mark.

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Section: Introductioncontrasting

confidence: 98%

¹H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives

Dubini

Korytiaková

Schinkel

et al. 2021

Preprint

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“…NMR is a powerful technique for the study of structure, dynamics, and folding of biomolecules such as nucleic acids [30] and proteins [31] . Hydrogen exchange measurement using NMR provides residue-specific information on the thermodynamics and kinetics of H-bonded secondary structure and exposure to solvent water.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of ice-binding and cryopreservation activities of type III antifreeze proteins

Choi

Lee

Seo

et al. 2021

Computational and Structural Biotechnology Journal

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“…Dynamics has been well studied in proteins, but relatively less is known about how dynamics and function are related in nucleic acids (33)(34)(35)(36)(37). One method to study the dynamics in nucleic acids is by measuring the k ex of the imino proton in base pairs with the bulk solvent (38). Previous studies have reported k ex values between 1 and 124 s À1 being detected by this method (39), with an upper exchange limit of 400 s À1 given for detection of an imino proton (40).…”

Section: Introductionmentioning

confidence: 99%

Reduction in Dynamics of Base pair Opening upon Ligand Binding by the Cocaine-Binding Aptamer

Churcher

Garaev

Hunter

et al. 2020

Biophysical Journal

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We have used magnetization transfer NMR experiments to measure the exchange rate constant (k ex ) of the imino protons in the unbound, cocaine-bound, and quinine-bound forms of the cocaine-binding DNA aptamer. Both long-stem 1 (MN4) and short-stem 1 (MN19) variants were analyzed, corresponding to structures with a prefolded secondary structure and ligandinduced-folding versions of this aptamer, respectively. The k ex values were measured as a function of temperature from 5 to 45 C to determine the thermodynamics of the base pair opening for MN4. We find that the base pairs close to the ligand-binding site become stronger upon ligand binding, whereas those located away from the binding site do not strengthen. With the buffer conditions used in this study, we observe imino 1 H signals in MN19 not previously seen, which leads us to conclude that in the free form, both stem 2 and parts of stem 3 are formed and that the base pairs in stem 1 become structured or more rigid upon binding. This is consistent with the k ex values for MN19 decreasing in both stem 1 and at the ligand-binding site. Based on the temperature dependence of the k ex values, we find that MN19 is more dynamic than MN4 in the free and both ligand-bound forms. For MN4, ligand-binding results in the reduction of dynamics that are localized to the binding site. These results demonstrate that an aptamer in which the base pairs are preformed also experiences a reduction in dynamics with ligand binding.

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Base-pair Opening Dynamics of Nucleic Acids in Relation to Their Biological Function

Cited by 15 publications

References 106 publications

¹H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives

¹H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives

Molecular basis of ice-binding and cryopreservation activities of type III antifreeze proteins

Reduction in Dynamics of Base pair Opening upon Ligand Binding by the Cocaine-Binding Aptamer

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Base-pair Opening Dynamics of Nucleic Acids in Relation to Their Biological Function

Cited by 15 publications

References 106 publications

1H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives

1H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives

Molecular basis of ice-binding and cryopreservation activities of type III antifreeze proteins

Reduction in Dynamics of Base pair Opening upon Ligand Binding by the Cocaine-Binding Aptamer

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Product

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¹H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives

¹H NMR chemical exchange techniques reveal local and global effects of oxidized cytosine derivatives