One-electron oxidation of TAT-motif triplex DNA and the ensuing Hoogsteen hydrogen-bonding dissociation

摘要

One-electron oxidation of adenine (A) leads initially to the formation of adenine radical cation (A(center dot+)). Subsequent deprotonation of A(center dot+) can provoke deoxyribonucleic acid (DNA) damage, which further causes senescence, cancer formation, and even cell death. However, compared with considerable reports on A(center dot+) reactions in free deoxyadenosine (dA) and duplex DNA, studies in non-B-form DNA that play critical biological roles are rare at present. It is thus of vital importance to explore non-B-form DNA, among which the triplex is an emerging topic. Herein, we investigate the deprotonation behavior of A(center dot+) in the TAT triplex with continuous A bases by time-resolved laser flash photolysis. The rate constants for the one-oxidation of triplex 8.4 x 10(8) M-1 s(-1) and A(center dot+) deprotonation 1.3 x 10(7) s(-1) are obtained. The kinetic isotope effect of A(center dot+) deprotonation in the TAT triplex is 1.8, which is characteristic of a direct release of the proton into the solvent similar to free base dA. It is thus elucidated that the A(center dot+) proton bound with the third strand is most likely to be released into the solvent because of the weaker Hoogsteen H-bonding interaction and the presence of the highly mobile hydration waters within the third strand. Additionally, it is confirmed through Fourier transform infrared spectroscopy that the deprotonation of A(center dot+) results in the dissociation of the third strand and disruption of the secondary structure of the triplex. These results provide valuable kinetic data and in-depth mechanistic insights for understanding the adenine oxidative DNA damage in the triplex.