Solvent Exposure Associated with Single Abasic Sites Alters the Base Sequence Dependence of Oxidation of Guanine in DNA in GG Sequence Contexts

Abstract

The effect of exposure of guanine in double-stranded oligonucleotides to aqueous solvent on its oxidation by one-electron oxidants was investigated by introducing single synthetic tetrahydrofuran-type abasic site (Ab) either adjacent to or opposite tandem GG sequences. The selective oxidation of guanine was initiated by photoexcitation of the aromatic sensitizers riboflavin and a pyrene derivative, and by the relatively small negatively charged carbonate radical anion. The relative rates of oxidation of the 5’-side and 3’-side G in runs of 5’-..GG.. (evaluated by standard hot alkali treatment of the damaged DNA strand followed by high resolution gel electrophoresis of the cleavage fragments) are markedly affected by adjacent abasic sites either on the same or opposite strand. For example, in fully double-stranded DNA or with Ab adjacent to the 5’-G, the 5’G/3’G damage ratio is ≥ 4, but is inverted (< 1.0) with Ab adjacent to the 3’-G. These striking effects of Ab are attributed to the preferential localization of the hole on the most solvent-exposed guanine regardless of the size, charge, or reduction potential of the oxidizing species.

Proton-coupled hole hopping in nucleosomal and free DNA initiated by site-specific hole injection

“…3 Further chemical transformations of radical intermediates yield a diverse spectrum of stable base modifications including alkali- and Fpg-labile lesions. 32–34 We find that the selective one-electron oxidation of guanine bases in nucleosomal DNA with CO 3 •− radicals does not, after treatment with hot piperidine, result in the appearance of the same kind of strong periodic cleavage patterns (Figure 3) that are observed in the case of direct strand breaks produced by • OH radicals (Figure 2C). One contributing factor could be that a hole generated in an “out” GGG position can be transferred to an adjacent “in” position.…”

“…2, 4 Our previous experiments have shown that CO 3 •− radicals selectively oxidize guanine bases in DNA to yield a spectrum of stable base modifications; these DNA lesions can be detected as strand breaks induced by the standard hot piperidine treatment or by incubation with the Fpg protein. 32–34 …”

“…In the presence of an excess of HCO 3 − anions, SO 4 •− radicals derived from the photo-induced dissociation of S 2 O 8 2− anions oxidize bicarbonate, thus generating CO 3 •− radicals. 32–34 The photochemically generated CO 3 •− radicals induce damage predominantly at the guanine sites in both nucleosomal and in free DNA (Figure 3). …”

G-Quadruplex Folds of the Human Telomere Sequence Alter the Site Reactivity and Reaction Pathway of Guanine Oxidation Compared to Duplex DNA

“…Further support for this hypothesis comes from solvent effects on G damage sites in DNA toroids, 119 and the observed increased reactivity of G toward oxidation with an adjacent abasic site. 118 These observations provide an additional parameter to consider beyond the sequence-dependent ionization potential for G 61, 110 in elucidating its oxidation pattern in the genome.…”

Sequence-Dependent Variation in the Reactivity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine toward Oxidation

“…One model to explain the sequence-selective oxidation of 8-oxodG by photoactivated riboflavin parallels that proposed for G oxidation by sulfate radical (${{\mathrm{SO}}_4}^{\underset{¯}{•}}$). 35 Both triplet riboflavin and ${{\mathrm{SO}}_4}^{\underset{¯}{•}}$ are strong oxidants (1.7 V and 2.4 V versus NHE, respectively; refs. 24,36) with the ability to remove electrons relatively indiscriminately from all four nucleobases.…”