Influence of an 8-oxoadenine lesion on the structural and dynamic features of a 30-mer DNA fragment with and without a mismatch

Barone, Flavia; Cellai, Luciano; Giordano, Cesare; Sala, Giuliana; Mazzei, Filomena

doi:10.1080/09553000110087353

Cited by 5 publications

(7 citation statements)

References 32 publications

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“…In this study, we are reporting on the biophysical properties of monomers and oligonucleotides of RNA containing the adenosine adduct 8‐oxoA. This lesion has been detected previously in both DNA and RNA . Studies on monomers of this lesion have shown that a conformational change around the glycosidic bond, anti→syn (Scheme , right), occurs upon oxidation of adenosine at the C8‐position, while equilibrium in adenosine favors the anti‐conformation.…”

Section: Introductionmentioning

confidence: 78%

Biophysical properties and thermal stability of oligonucleotides of RNA containing 7,8‐dihydro‐8‐hydroxyadenosine

2014

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Circular dichroism (CD) was used to assess the stabilization/destabilization imposed by oxidative lesion 7,8-dihydro-8-hydroxyadenosine (8-oxoA) on strands of RNA with different structural motifs. RNA:RNA homoduplex destabilization was observed in a position dependent manner using 10-mers as models that displayed differences between 12.7 and 15.1°C. We found that increasing the number of modifications resulted in depressed Tm values of about 12–15°C per lesion. The same effect was observed on RNA:DNA heteroduplex samples. We also tested the effects of this lesion in short hairpins containing the tetraloop UUCX (X = A, 8-oxoA). We found that the stem was hypersensitive to substitution of A by 8-oxoA and that it destabilized the structure by >23°C. Concomitant substitution at the stem and loop prevented formation of this secondary structure or lead to other less-stable hairpins. Incorporation of this lesion at the first base of the loop had no effect on either structure. Overall, we found that the effects of 8-oxoA on RNA structure are position dependent and that its stabilization may vary from sharp decreases to small increments, in some cases, leading to the formation of other more/less stable structures. These structural changes may have larger biological implications, particularly if the oxidatively modified RNA persists, thus leading to changes in RNA reactivity and function. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 167–174, 2015.

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Section: Introductionmentioning

confidence: 78%

Biophysical properties and thermal stability of oligonucleotides of RNA containing 7,8‐dihydro‐8‐hydroxyadenosine

2014

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“…Some moderate distinctions in the backbone structure of the oligonucleotide containing 8-oxoA:T pair, compare to the A:T pair, were captured with Fourier transform-infrared spectroscopy [32]. In addition, fine structure analysis of the DNA duplex with 8-oxoA:C pair, in contrast to A:T, 8-oxoA:T, and A:C pairs, demonstrated notable structural and dynamic differences [31]. The spatial structure of the damaged region can also influence the recognition by DNA metabolism enzymes [29].…”

Section: Mutagenic Potential Of 8-oxoamentioning

confidence: 99%

“…The Watson-Crick face of 8-oxoA remains intact allowing the formation of a stable base pair with thymine (Figure 3A). According to NMR and thermal melting studies, the 8-oxoA:T pair does not substantially disrupt the helix geometry [30] but slightly decreases T m (by 1.7 • C in a 30-bp duplex) [31]. Some moderate distinctions in the backbone structure of the oligonucleotide containing 8-oxoA:T pair, compare to the A:T pair, were captured with Fourier transform-infrared spectroscopy [32].…”

Section: Mutagenic Potential Of 8-oxoamentioning

confidence: 99%

“…The spatial structure of the damaged region can also influence the recognition by DNA metabolism enzymes [29]. Indeed, the presence of few mismatches with 8-oxoA impedes the recognition of the damaged site by DNA glycosylases (see Section 4) [31]. It is likely that the mild distortion of the conformational geometry of the sugar-phosphate backbone caused by 8-oxoA in DNA might in some degree inhibit the activity of at least high-fidelity DNA polymerases.…”

Section: Mutagenic Potential Of 8-oxoamentioning

confidence: 99%

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8-Oxoadenine: A «New» Player of the Oxidative Stress in Mammals?

Kruchinin,

Kamzeeva,

Zharkov

et al. 2024

IJMS

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Numerous studies have shown that oxidative modifications of guanine (7,8-dihydro-8-oxoguanine, 8-oxoG) can affect cellular functions. 7,8-Dihydro-8-oxoadenine (8-oxoA) is another abundant paradigmatic ambiguous nucleobase but findings reported on the mutagenicity of 8-oxoA in bacterial and eukaryotic cells are incomplete and contradictory. Although several genotoxic studies have demonstrated the mutagenic potential of 8-oxoA in eukaryotic cells, very little biochemical and bioinformatics data about the mechanism of 8-oxoA-induced mutagenesis are available. In this review, we discuss dual coding properties of 8-oxoA, summarize historical and recent genotoxicity and biochemical studies, and address the main protective cellular mechanisms of response to 8-oxoA. We also discuss the available structural data for 8-oxoA bypass by different DNA polymerases as well as the mechanisms of 8-oxoA recognition by DNA repair enzymes.

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“…OA, with an amino group at C6, preferentially pairs with T in an anti-anti conformation, although it can also mispair with G, leading to A→C transversions (52,53). The OA·C mismatch was also observed in a syn-anti conformation that distorts the DNA duplex (54,55). In this work, a comparison of ligation efficiency with different oxidized lesions provides information concerning the influence of purine modifications on base stacking and base pairing related to enzyme activity.…”

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confidence: 99%

In Vitro Ligation of Oligodeoxynucleotides Containing C8-Oxidized Purine Lesions Using Bacteriophage T4 DNA Ligase

et al. 2007

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Ligases conduct the final stage of repair of DNA damage by sealing a single-stranded nick after excision of damaged nucleotides and reinsertion of correct nucleotides. Depending upon the circumstances and the success of the repair process, lesions may remain at the ligation site, either in the template or at the oligomer termini to be joined. Ligation experiments using bacteriophage T4 DNA ligase were carried out with purine lesions in four positions surrounding the nick site in a total of 96 different duplexes. The oxidized lesion 8-oxo-7,8-dihydroguanosine (OG) showed, as expected, that the enzyme is most sensitive to lesions on the 3′ end of the nick compared to the 5′ end and to lesions located in the intact template strand. In general, substrates containing the OG·A mismatch were more readily ligated than OG·C. Ligations of duplexes containing the OA·T base pair (OA=8-oxo-7,8-dihydroadenosine) that could adopt an anti-anti conformation proceeded in high efficiencies. An OI·Acontaining duplex (OI = 8-oxo-7,8-dihydroinosine) behaved similarly to OG·A. Due to its low reduction potential, OG is readily oxidized to secondary oxidation products, such as the guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) nucleosides; these lesions also contain an oxo group at the original C8 position of the purine. Ligation of oligomers containing Gh and Sp occurred when opposite A and G although the overall ligation efficiencies were much lower than most OG base pairs. Steady-state kinetic studies were carried out for representative examples of lesions in the template. K m increased by 90-100-fold for OG·C, OI·C, OI·A and OA·T containing duplexes compared to G·C. Substrates containing Gh·A, Gh·G, Sp·A and Sp·G base pairs showed K m values 20-70-fold higher than G·C while the K m value for OG·A was 5 times lower than G·C.Reactive oxygen species (ROS) 1 such as O 2 −•, HO• and H 2 O 2 are continuously produced during normal metabolic processes, and their production is augmented by inflammation and exposure to certain agents (1,2). DNA is sensitive to ROS, and in vivo oxidative damage results in DNA strand breaks, base modifications and DNA-protein cross-links (1). Unrepaired oxidative DNA damage can be mutagenic and is implicated in carcinogenesis, neurological disorders and aging (2-4). Oxidation of guanine, the most easily oxidized nucleobase (5), can lead to the commonly observed lesion 8-oxo-7,8-dihydro-2′-deoxyguanosine (OG) which is regarded as a biomarker of oxidative DNA damage in the cell (6). OG is mutagenic in the absence of repair leading to G→T transversions (7-10).OG can be removed by the base excision repair pathway (BER) (11-14) involving glycosidic bond cleavage of the damaged base followed by excision of the remaining abasic (AP) site (15). A nucleotide is inserted by a DNA polymerase, and in a final stage, the nick is sealed by a DNA ligase (16)(17)(18)(19)(20). Although DNA repair of oxidized base lesions has been extensively

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Influence of an 8-oxoadenine lesion on the structural and dynamic features of a 30-mer DNA fragment with and without a mismatch

Cited by 5 publications

References 32 publications

Biophysical properties and thermal stability of oligonucleotides of RNA containing 7,8‐dihydro‐8‐hydroxyadenosine

Biophysical properties and thermal stability of oligonucleotides of RNA containing 7,8‐dihydro‐8‐hydroxyadenosine

8-Oxoadenine: A «New» Player of the Oxidative Stress in Mammals?

In Vitro Ligation of Oligodeoxynucleotides Containing C8-Oxidized Purine Lesions Using Bacteriophage T4 DNA Ligase

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