Structure and Dynamics of DNA Duplexes Containing a Cluster of Mutagenic 8-Oxoguanine and Abasic Site Lesions

Zalesak, Jan; Lourdin, Morgane; Krejčí, Lumír; Constant, Jean‐François; Jourdan, Muriel

doi:10.1016/j.jmb.2013.12.022

Cited by 19 publications

(19 citation statements)

References 41 publications

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“…3, with the sugar of the abasic site flipping in and out of the duplex, in accord with NMR data and theoretical simulations performed for an unpaired G in the same CGC 25,27 or similar CGT contexts. 36 When the unpaired guanine is flanked by other G bases (GX system), both force fields again predict intrahelical conformations, in accord with previous studies of unpaired guanines in GGG 27,37 or GGA sequences.…”

Section: Dna Structuresupporting

confidence: 85%

“…28 In a recent study, NMR and constrained MD simulations also pointed to such non-Watson-Crick pattern for the same GGG sequence when a 2′- Please do not adjust margins Please do not adjust margins deoxyribose abasic site was considered, whereas, for its chemically stable analogue tetrahydrofuran, as used here, the standard Watson-Crick pattern was kept. 37 We note however that the sequence of the DNA in that study differs from the one considered here and contained also an additional 8oxoguanine lesion.…”

mentioning

confidence: 63%

“…38 We adopted the prototypical abasic site, tetrahydrofuran (X), commonly used as a model for enzymatically generated abasic sites, which exist as mixtures of α and β hemiacetals, due to its chemical stability. 28,37 MD simulations were performed starting from standard B-DNA fiber geometries created using the NAB module of the Amber12 software, 39 eventually modified in order to delete a C or G nucleobase and generate the abasic site. The systems were neutralized adding Na+ ions 40 and solvated in a truncated octahedron box of TIP3P water (buffer region 14 Å).…”

Section: Simulationsmentioning

confidence: 99%

“…The impact of abasic sites on the structure and flexibility of DNA has been investigated both using theoretical models and NMR spectroscopy. [25][26][27][28][29][30][31][32][33][34][35][36][37] The bulk of these studies indicate that the overall B-DNA structure of the duplex is maintained in the presence of an abasic site. However, the lesion increases structural flexibility, and the local conformation of the unpaired base depends on its nature and its sequence context.…”

Section: Dna Structurementioning

confidence: 99%

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How abasic sites impact hole transfer dynamics in GC-rich DNA sequences

Corbella

Voityuk

Curutchet

2018

Phys. Chem. Chem. Phys.

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Changes in DNA charge transfer properties upon the creation of apurinic and apyrimidinic sites have been used to monitor DNA repair processes, given that such lesions generally reduce charge transfer yields. However, because these lesions translate into distinct intra and extrahelical conformations depending on the nature of the unpaired base and its DNA context, it is unclear the actual impact of such diverse conformations on charge transfer. Here we combine classical molecular dynamics, quantum/molecular mechanics (QM/MM) calculations, and kinetic Monte Carlo simulations to investigate the impact of abasic sites on the structure and hole transfer (HT) properties of DNA. We consider both apurinic and apyrimidinic sites in polyG and polyGC sequences and find that most situations lead to intrahelical conformations where HT rates are significantly slowed down due to the energetic disorder induced by the abasic void. In contrast, the presence of an unpaired C flanked by C bases leads to an extrahelical conformation where stacking among G sites is reduced, leading to an attenuation of electronic couplings and a destabilization of hole states. Interestingly, this leads to an asymmetric HT behavior, given that the 5' to 3' transfer along the G strand is slowed down by one order of magnitude while the opposite 3' to 5' transfer remains similar to that estimated for the reference polyG sequence. Our simulations thus suggest that electrochemical monitoring of the DNA repair process following changes in charge transfer properties can miss repair events linked to abasic sites adopting extrahelical conformations.

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Section: Dna Structuresupporting

confidence: 85%

mentioning

confidence: 63%

Section: Simulationsmentioning

confidence: 99%

Section: Dna Structurementioning

confidence: 99%

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How abasic sites impact hole transfer dynamics in GC-rich DNA sequences

Corbella

Voityuk

Curutchet

2018

Phys. Chem. Chem. Phys.

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“…The possibility that greater single strandedness and/or flexibility enhances AP reactivity is reinforced by the increased rate constant when the gap is increased from 1 bp ( 7 ) to 2 bp ( 10 ) (Table 2) and is consistent with recent nuclear magnetic resonance studies on abasic site-containing clustered lesions. 52,53 In addition, the rapid decrease in the rate constant for AP 89 reactivity as the distance between the single-nucleotide gap and the abasic site increases from 3 to 7 bp is also consistent with the single-stranded nature of the DNA contributing to reactivity. We hypothesize that the increased single strandedness and/or flexibility of the bistranded lesion allows the strand containing AP to adopt conformations that are conducive to reaction with the histone tail that is responsible for cleavage catalysis.…”

Section: Discussionsupporting

confidence: 56%

Probing Enhanced Double-Strand Break Formation at Abasic Sites within Clustered Lesions in Nucleosome Core Particles

et al. 2016

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DNA is rapidly cleaved under mild alkaline conditions at apyrimidinic/apurinic sites, but the half-life is several weeks in phosphate buffer (pH 7.5). However, abasic sites are ~100-fold more reactive within nucleosome core particles (NCPs). Histone proteins catalyze the strand scission, and at superhelical location 1.5, the histone H4 tail is largely responsible for the accelerated cleavage. The rate constant for strand scission at an abasic site is enhanced further in a nucleosome core particle when it is part of a bistranded lesion containing a proximal strand break. Cleavage of this form results in a highly deleterious double-strand break. This acceleration is dependent upon the position of the abasic lesion in the NCP and its structure. The enhancement in cleavage rate at an apurinic/apyrimidinic site rapidly drops off as the distance between the strand break and abasic site increases and is negligible once the two forms of damage are separated by 7 bp. However, the enhancement of the rate of double-strand break formation increases when the size of the gap is increased from one to two nucleotides. In contrast, the cleavage rate enhancement at 2-deoxyribonolactone within bistranded lesions is more modest, and it is similar in free DNA and nucleosome core particles. We postulate that the enhanced rate of double-strand break formation at bistranded lesions containing apurinic/apyrimidinic sites within nucleosome core particles is a general phenomenon and is due to increased DNA flexibility.

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