Abstract
Oligonucleotides tethered by an alkylene linkage between the O(6) -atoms of two consecutive 2'-deoxyguanosines, which lack a phosphodiester linkage between these residues, have been synthesized as a model system of intrastrand cross-linked (IaCL) DNA. UV thermal denaturation studies of duplexes formed between these butylene- and heptylene-linked oligonucleotides with their complementary DNA sequences revealed about 20 °C reduction in stability relative to the unmodified duplex. Circular dichroism spectra of the model IaCL duplexes displayed a signature characteristic of B-form DNA, suggesting minimal global perturbations are induced by the lesion. The model IaCL containing duplexes were investigated as substrates of O(6) -alkylguanine DNA alkyltransferase (AGT) proteins from human and E. coli (Ada-C and OGT). Human AGT was found to repair both model IaCL duplexes with greater efficiency towards the heptylene versus butylene analog adding to our knowledge of substrates this protein can repair.
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