Abstract
DNA interstrand crosslinks (ICLs) are the primary mechanism for the cytotoxic activity of many clinical anticancer drugs, and numerous strategies for forming ICLs have been developed. One such method is using crosslink-forming oligonucleotides (CFOs). In this study, we designed a 4-amino-6-oxo-2-vinylpyrimidine (AOVP) derivative with an acyclic spacer to react selectively with guanine. The AOVP CFO exhibited selective crosslinking reactivity with guanine and thymine in DNA, and with guanine in RNA. These crosslinking reactions with guanine were accelerated in the presence of CoCl2, NiCl2, ZnCl2 and MnCl2. In addition, we demonstrated that the AOVP CFO was reactive toward 8-oxoguanine opposite AOVP in the duplex DNA. The structural analysis of each guanine and 8-oxoguanine adduct in the duplex DNA was investigated by high-resolution NMR. The results suggested that AOVP reacts at the N2 amine in guanine and at the N1 or N2 amines in 8-oxoguanine in the duplex DNA. This study demonstrated the first direct determination of the adduct structure in duplex DNA without enzyme digestion.
Highlights
Strategies for preparing crosslinked duplex DNA have attracted attention due to their many applications in a variety of fields, including DNA repair, gene regulation and nanotechnology
Oligonucleotides (ODNs) containing O6-guanine-alkyl-O6-guanine interstrand crosslinks (ICLs) products were used to investigate the repair of DNA ICLs by O6-alkylguanineDNA alkyltransferase [16,17]
ICL duplex DNA has been synthesized by disulfide bond linkage [21,27], click chemistry [25,26] and amide bond formation [22]
Summary
Strategies for preparing crosslinked duplex DNA have attracted attention due to their many applications in a variety of fields, including DNA repair, gene regulation and nanotechnology. ICL duplex DNA has been synthesized by disulfide bond linkage [21,27], click chemistry [25,26] and amide bond formation [22] These strategies produced a variety of ICL duplex DNA structures by adjusting the linker length between the DNA strand and each reactive moiety and these strategies were used to form the DNA nanostructure. These methods for preparing ICL duplex DNA could not be used to control gene regulation.
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