DNA Damage Processing by Human 8-Oxoguanine-DNA Glycosylase Mutants with the Occluded Active Site

Lukina, M. V.; Popov, A.; Koval, Vladimir V.; Vorobjev, Yury N.; Fedorova, Olga S.; Zharkov, Dmitry O.

doi:10.1074/jbc.m113.487322

Cited by 24 publications

(28 citation statements)

References 45 publications

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“…Our data suggest that although Gly42 provides the sole interaction that structurally discriminates 8-oxoG and G in the active site, it may be strong enough to keep G from entering the active site as deeply as does 8-oxoG (Figure 10C). Experimental studies have shown that the Gln315Phe, Gln315Trp, Cys253Ile, and Cys253Leu mutations, which perturb the active site disposition of 8-oxoG but not expel it altogether, can severely reduce the catalytic activity of OGG1, 16, 44 thus suggesting that the catalysis of base excision by OGG1 requires very precise positioning of the reacting moieties. Therefore, the unfavorable interaction of Gly42 may prevent G from achieving the optimal position for catalysis, and thus the active site geometry constitutes the final damage checkpoint of OGG1.…”

Section: Resultsmentioning

confidence: 99%

DNA Deformation-Coupled Recognition of 8-Oxoguanine: Conformational Kinetic Gating in Human DNA Glycosylase

Li¹,

Endutkin

Bergonzo³

et al. 2017

J. Am. Chem. Soc.

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8-Oxoguanine (8-oxoG), a mutagenic DNA lesion generated under oxidative stress, differs from its precursor guanine by only two substitutions (O8 andH7). Human 8-oxoguanine glycosylase 1 (OGG1) can locate and remove 8-oxoG through extrusion and excision. To date, it remains unclear how OGG1 efficiently distinguishes 8-oxoG from a large excess of undamaged DNA bases. We recently showed that formamidopyrimidine–DNA glycosylase (Fpg), a bacterial functional analog of OGG1, can selectively facilitate eversion of oxoG by stabilizing several intermediate states, and it is intriguing whether OGG1 also employs a similar mechanism in lesion recognition. Here, we use molecular dynamics simulations to explore the mechanism by which OGG1 discriminates between 8-oxoG and guanine along the base eversion pathway. The MD results suggest an important role for kinking of the DNA by the glycosylase, which positions DNA phosphates in a way that assists lesion recognition during base eversion. The computational predictions were validated through experimental enzyme assays on phosphorothioate substrate analogs. Our simulations suggest that OGG1 distinguishes between 8-oxoG and G using their chemical dissimilarities not only at the active site, but also at earlier stages during base eversion, and this mechanism is at least partially conserved in Fpg despite lack of structural homology. The similarity also suggests that lesion recognition through multiple gating steps may be a common theme in DNA repair. Our results provide new insight into how enzymes can exploit kinetics and DNA conformational changes to probe the chemical modifications present in DNA lesions.

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Section: Resultsmentioning

confidence: 99%

DNA Deformation-Coupled Recognition of 8-Oxoguanine: Conformational Kinetic Gating in Human DNA Glycosylase

Li¹,

Endutkin

Bergonzo³

et al. 2017

J. Am. Chem. Soc.

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“…Lukina et al [ 50 ] engineered C253L and C253I mutant hOGG1 forms with an occluded active site pocket by replacement of a Cys253 to a bulky leucine or isoleucine. Despite the perturbed active site geometry afforded by this mutation and dramatic decline in catalytic activity, the enzyme was still catalytically active.…”

Section: Recognition Of 8-oxogmentioning

confidence: 99%

Structural Features of the Interaction between Human 8-Oxoguanine DNA Glycosylase hOGG1 and DNA

Koval¹,

Knorre²,

Fedorova³

2014

Acta Naturae

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The purpose of the present review is to summarize the data related with the structural features of interaction between the human repair enzyme 8-oxoguanine DNA glycosylase (hOGG1) and DNA. The review covers the questions concerning the role of individual amino acids of hOGG1 in the specific recognition of the oxidized DNA bases, formation of the enzyme–substrate complex, and excision of the lesion bases from DNA. Attention is also focused upon conformational changes in the enzyme active site and disruption of enzyme activity as a result of amino acid mutations. The mechanism of damaged bases release from DNA induced by hOGG1 is discussed in the context of structural dynamics.

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“…The Watson-Crick edge is recognized by Gln315 through two direct hydrogen bonds and a water bridge. Replacement of Cys253 or Gln315 with bulkier side chains strongly interferes with oxoG excision but affects the abasic site site cleavage to a much lower degree [121,122]. Given that the electric dipoles of G and oxoG are almost opposite, and that 7-deazaguanine and 7-deaza-8-azaguanine cannot form bonds to Gly42 but still efficiently enter the active site [120], it seems that stabilization of oxoG in the active site pocket is not limited to hydrogen bonding but to a significant degree relies on hydrophobic and electrostatic interactions with the enzyme.…”

Section: Ogg1mentioning

confidence: 99%

“…An extended series of structures of Fpg [102][103][104][105][127][128][129][130][131] and OGG1 [110,120,121,123,[132][133][134][135][136][137][138], together with molecular dynamic simulation of conformational transition between these intermediates [139][140][141][142], and stopped-flow studies [115,122,140,[143][144][145][146][147][148][149][150] produced a multistep oxoG recognition model that turned out to be surprisingly similar for these two enzymes despite their structural dissimilarity. Both Fpg and OGG1 kink DNA by 40 • -50 • and insert an aromatic wedge (Phe or Tyr) into the base stack, causing the sampled base pair to buckle.…”

Section: Dynamic Oxog Recognitionmentioning

confidence: 99%

Reading and Misreading 8-oxoguanine, a Paradigmatic Ambiguous Nucleobase

et al. 2019

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7,8-Dihydro-8-oxoguanine (oxoG) is the most abundant oxidative DNA lesion with dual coding properties. It forms both Watson–Crick (anti)oxoG:(anti)C and Hoogsteen (syn)oxoG:(anti)A base pairs without a significant distortion of a B-DNA helix. DNA polymerases bypass oxoG but the accuracy of nucleotide incorporation opposite the lesion varies depending on the polymerase-specific interactions with the templating oxoG and incoming nucleotides. High-fidelity replicative DNA polymerases read oxoG as a cognate base for A while treating oxoG:C as a mismatch. The mutagenic effects of oxoG in the cell are alleviated by specific systems for DNA repair and nucleotide pool sanitization, preventing mutagenesis from both direct DNA oxidation and oxodGMP incorporation. DNA translesion synthesis could provide an additional protective mechanism against oxoG mutagenesis in cells. Several human DNA polymerases of the X- and Y-families efficiently and accurately incorporate nucleotides opposite oxoG. In this review, we address the mutagenic potential of oxoG in cells and discuss the structural basis for oxoG bypass by different DNA polymerases and the mechanisms of the recognition of oxoG by DNA glycosylases and dNTP hydrolases.

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DNA Damage Processing by Human 8-Oxoguanine-DNA Glycosylase Mutants with the Occluded Active Site

Cited by 24 publications

References 45 publications

DNA Deformation-Coupled Recognition of 8-Oxoguanine: Conformational Kinetic Gating in Human DNA Glycosylase

DNA Deformation-Coupled Recognition of 8-Oxoguanine: Conformational Kinetic Gating in Human DNA Glycosylase

Structural Features of the Interaction between Human 8-Oxoguanine DNA Glycosylase hOGG1 and DNA

Reading and Misreading 8-oxoguanine, a Paradigmatic Ambiguous Nucleobase

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