Effect of 8-Oxoguanine on DNA Structure and Deformability

Dršata, Tomáš; Kara, Mahmut; Zacharias, Martin; Lankaš, Filip

doi:10.1021/jp407562t

Cited by 19 publications

(18 citation statements)

References 44 publications

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“…In previous simulations we found that the presence of 8oxoG in DNA can result in local alterations of the backbone and sugar pucker fine structure (13,14). However, no significant differences in the helical deformability including twist deformability were observed (14). This is supported by experimental crystal structures of 8oxoG containing DNA that also indicate distinct changes in the nucleo-backbone structure compared to undamaged DNA.…”

Section: Discussionmentioning

confidence: 91%

Global deformation facilitates flipping of damaged 8-oxo-guanine and guanine in DNA

Rosa¹,

Zacharias²

2016

Nucleic Acids Res

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Oxidation of guanine (Gua) to form 7,8-dihydro-8-oxoguanine (8oxoG) is a frequent mutagenic DNA lesion. DNA repair glycosylases such as the bacterial MutM can effciently recognize and eliminate the 8oxoG damage by base excision. The base excision requires a 8oxoG looping out (flipping) from an intrahelical base paired to an extrahelical state where the damaged base is in the enzyme active site. It is still unclear how the damage is identified and flipped from an energetically stable stacked and paired state without any external energy source. Free energy simulations have been employed to study the flipping process for globally deformed DNA conformational states. DNA deformations were generated by systematically untwisting the DNA to mimic its conformation in repair enzyme encounter complex. The simulations indicate that global DNA untwisting deformation toward the enzyme bound form alone (without protein) significantly reduces the penalty for damage flipping to about half of the penalty observed in regular DNA. The finding offers a mechanistic explanation how binding free energy that is transformed to binding induced DNA deformation facilitates flipping and helps to rapidly detect a damaged base. It is likely of general relevance since repair enzyme binding frequently results in significant deformation of the target DNA.

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Section: Discussionmentioning

confidence: 91%

Global deformation facilitates flipping of damaged 8-oxo-guanine and guanine in DNA

Rosa¹,

Zacharias²

2016

Nucleic Acids Res

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“…T 19 UMe 98 1 1 0 HMe 97 1 2 0 FMe 95 3 2 0 T 7 C 8 /G 17 A 18 UMe 68 20 9 3 HMe 56 31 8 5 FMe 63 25 6 6 42°for HMe, 40°for FMe). A correlation between twist and mixed state populations has been observed in other sequences before [20,31,55]. HMe had the highest value of twist and the highest population of mixed BI/BII states (39%) at the T 7 C 8 /G 17 A 18 step.…”

Section: Resultsmentioning

confidence: 52%

BII stability and base step flexibility of N6-adenine methylated GATC motifs

Karolak

Vaart

2015

Biophysical Chemistry

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The effect of N6-adenine methylation on the flexibility and shape of palindromic GATC sequences has been investigated by molecular dynamics simulations. Variations in DNA backbone geometry were observed, which were dependent on the degree of methylation and the identity of the bases. While the effect was small, more frequent BI to BII conversions were observed in the GA step of hemimethylated DNA. The increased BII population of the hemimethylated system positively correlated with increased stacking interactions between methylated adenine and guanine, while stacking interactions decreased at the TC step for the fully methylated strand. The flexibility of the AT and TC steps was marginally affected by methylation, in a fashion that was correlated with stacking interactions. The facilitated BI to BII conversion in hemimethylated strands might be of importance for SeqA selectivity and binding.

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“…The trajectories are used to extract the variances and covariances of all intra‐ and interhelical parameters associated with the sampled DNA conformations resulting in a stiffness matrix to describe the deformability of the duplex in terms of effective force constants for helical deformations. Details of the approach have been described in previous publications . The overall stiffness is characterized by conformational entropy per rigid base coordinate, as described earlier …”

Section: Methodsmentioning

confidence: 99%

Effect O6‐guanine alkylation on DNA flexibility studied by comparative molecular dynamics simulations

et al. 2014

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Alkylation of guanine at the O6 atom is a highly mutagenic DNA lesion because it alters the coding specificity of the base causing G:C to A:T transversion mutations. Specific DNA repair enzymes, e.g. O(6)-alkylguanin-DNA-Transferases (AGT), recognize and repair such damage after looping out the damaged base to transfer it into the enzyme active site. The exact mechanism how the repair enzyme identifies a damaged site within a large surplus of undamaged DNA is not fully understood. The O(6)-alkylation of guanine may change the deformability of DNA which may facilitate the initial binding of a repair enzyme at the damaged site. In order to characterize the effect of O(6)-methyl-guanine (O(6)-MeG) containing base pairs on the DNA deformability extensive comparative molecular dynamics (MD) simulations on duplex DNA with central G:C, O(6)-MeG:C or O(6)-MeG:T base pairs were performed. The simulations indicate significant differences in the helical deformability due to the presence of O(6)-MeG compared to regular undamaged DNA. This includes enhanced base pair opening, shear and stagger motions and alterations in the backbone fine structure caused in part by transient rupture of the base pairing at the damaged site and transient insertion of water molecules. It is likely that the increased opening motions of O(6)-MeG:C or O(6)-MeG:T base pairs play a decisive role for the induced fit recognition or for the looping out of the damaged base by repair enzymes.

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Effect of 8-Oxoguanine on DNA Structure and Deformability

Cited by 19 publications

References 44 publications

Global deformation facilitates flipping of damaged 8-oxo-guanine and guanine in DNA

Global deformation facilitates flipping of damaged 8-oxo-guanine and guanine in DNA

BII stability and base step flexibility of N6-adenine methylated GATC motifs

Effect O6‐guanine alkylation on DNA flexibility studied by comparative molecular dynamics simulations

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