Open AccessSulfur-centered hemi-bond radicals as active intermediates in S-DNA phosphorothioate oxidation
Author(s) -
Jialong Jie,
Ye Xia,
Chunhua Huang,
Hongmei Zhao,
Chunfan Yang,
Kunhui Liu,
Dong Joo Song,
Ben-Zhan Zhu,
Hongmei Su
Publication year - 2019
Publication title -
nucleic acids research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.008
H-Index - 537
eISSN - 1362-4954
pISSN - 0305-1048
DOI - 10.1093/nar/gkz987
Subject(s) - guanine , dna , biology , radical , dna damage , cytosine , base pair , moiety , sulfur , dna oxidation , biochemistry , biophysics , stereochemistry , nucleotide , chemistry , gene , organic chemistry
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.