title: O(6)-Alkylguanine DNA Alkyltransferase Repair Activity Towards Intrastrand Cross-Linked DNA is Influenced by the Internucleotide Linkage.
abstract: Oligonucleotides containing an alkylene intrastrand cross-link (IaCL) between the O(6) -atoms of two consecutive 2'-deoxyguanosines (dG) were prepared by solid-phase synthesis. UV thermal denaturation studies of duplexes containing butylene and heptylene IaCL revealed a 20 °C reduction in stability compared to the unmodified duplexes. Circular dichroism profiles of these IaCL DNA duplexes exhibited signatures consistent with B-form DNA. Human O(6) -alkylguanine DNA alkyltransferase (hAGT) was capable of repairing both IaCL containing duplexes with slightly greater efficiency towards the heptylene analog. Interestingly, repair efficiencies of hAGT towards these IaCL were lower compared to O(6) -alkylene linked IaCL lacking the 5'-3'-phosphodiester linkage between the connected 2'-deoxyguanosine residues. These results demonstrate that the proficiency of hAGT activity towards IaCL at the O(6) -atom of dG is influenced by the backbone phosphodiester linkage between the cross-linked residues.
authors.affiliation: Department of Chemistry&Biochemistry, Concordia University, 7141 Sherbrooke St. West, Montréal, Québec (Canada.
authors.forename: Derek K
authors.initials: DK
authors.lastname: O'Flaherty
authors.affiliation: Department of Chemistry&Biochemistry, Concordia University, 7141 Sherbrooke St. West, Montréal, Québec (Canada. Chris.Wilds@concordia.ca.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilds
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D009691:Nucleic Acid Denaturation / Q000528:radiation effects; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D013696:Temperature; D014466:Ultraviolet Rays
chemical_list: D018736:DNA Adducts; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase
keywords: DNA damage; DNA repair; O6-alkylguanine DNA alkyltransferase; intrastrand cross-link; oligonucleotides