Selective one-electron oxidation of duplex DNA oligomers: reaction at thymines

Abstract

The one-electron oxidation of duplex DNA generates a nucleobase radical cation (electron "hole") that migrates long distances by a hopping mechanism. The radical cation reacts irreversibly with H2O or O2 to form oxidation products (damaged bases). In normal DNA (containing the four common DNA bases), reaction occurs most frequently at guanine. However, in DNA duplexes that do not contain guanine (i.e., those comprised exclusively of A/T base pairs), we discovered that reaction occurs primarily at thymine and gives products resulting from oxidation of the T-C5 methyl group and from addition to its C5-C6 double bond. This surprising result shows that it is the relative reactivity, not the stability, of a nucleobase radical cation that determines the nature of the products formed from oxidation of DNA. A mechanism for reaction is proposed whereby a thymine radical cation may either lose a proton from its methyl group or H2O/O2 may add across its double bond. In the latter case, addition may initiate a tandem reaction that converts both thymines of a TT step to oxidation products.

The influence of the phosphorothioate diester bond on the DNA oxidation process

“…This observation may be supported by previous data, however, for the induction of a T lesion, a TT sequence is necessary [31].…”

“…In the case of the two other thymidine lesions located at positions T21 and T19, the neighbouring thymine was not present, which is in opposition to the above-mentioned requirement [31]. The next section of discussed strand consists of AAA accomplishing the role of shutter, which has been previously proven [30,32].…”

“…On the other hand, Schuster has shown that the G nearest to to antrachinone is mainly oxidised [35]. It should be pointed out that Cadet et al investigated the A/T oligonucleotides with and without the GG segment [31]. In the first case, the hole trapping occurred at T, while in the second, as expected, G was the most reactive site.…”

“…However, the lack of 8-oxoG formation is in opposition to the widely accepted theory. In the currently studied oligonucleotides only two isolated Gs are present, instead of GG [31]. Moreover, in 5'-TGT-3', the unfavourable neighbourhood of G possesses 0.48/0.09 eV higher effective energy of the positive charge than 5'-AGG-3' or 5'-GGT-3', respectively [33].…”

Electrocatalytic activity of thianthrene toward one-electron oxidation of guanosine and DNA in a non-aqueous medium

“…Less than a decade after discovering structural features of DNA double helix [5], the first experiments to answer how charge can be transported through DNA chains were carried out [6][7][8] but this question is still debated [9][10][11][12] and DNA was described as an insulator, semiconductor, or molecular wire. Extensive experimentation has shown that the radical cation (electron ''hole") is introduced into a duplex DNA oligomer in solution by one-electron oxidation of guanosine.…”