Sulfur-centered hemi-bond radicals as active intermediates in S-DNA phosphorothioate oxidation.

ABSTRACT: Phosphorothioate (PS) modifications naturally appear in bacteria and archaea genome and are widely used as antisense strategy in gene therapy. But the chemical effects of PS introduction as a redox active site into DNA (S-DNA) is still poorly understood. Herein, we perform time-resolved spectroscopy to examine the underlying mechanisms and dynamics of the PS oxidation by potent radicals in free model, in dinucleotide, and in S-oligomer. The crucial sulphur-centered hemi-bonded intermediates -P-S?S-P- were observed and found to play critical roles leading to the stable adducts of -P-S-S-P-, which are backbone DNA lesion products. Moreover, the oxidation of the PS moiety in dinucleotides d[GPSG], d[APSA], d[GPSA], d[APSG] and in S-oligomers was monitored in real-time, showing that PS oxidation can compete with adenine but not with guanine. Significantly, hole transfer process from A+• to PS and concomitant -P-S?S-P- formation was observed, demonstrating the base-to-backbone hole transfer unique to S-DNA, which is different from the normally adopted backbone-to-base hole transfer in native DNA. These findings reveal the distinct backbone lesion pathway brought by the PS modification and also imply an alternative -P-S?S-P-/-P-S-S-P- pathway accounting for the interesting protective role of PS as an oxidation sacrifice in bacterial genome.

SUBMITTER: Jie J 

PROVIDER: S-EPMC7145531 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature