title: DNA cleavage at the AP site via β-elimination mediated by the AP site-binding ligands.
abstract: DNA is continuously damaged by endogenous and exogenous factors such as oxidation and alkylation. In the base excision repair pathway, the damaged nucleobases are removed by DNA N-glycosylase to form the abasic sites (AP sites). The alkylating antitumor agent exhibits cytotoxicity through the formation of the AP site. Therefore blockage or modulation of the AP site repair pathway may enhance the antitumor efficacy of DNA alkylating agents. In this study, we have examined the effects of the nucleobase-polyamine conjugated ligands (G-, A-, C- and T-ligands) on the cleavage of the AP site. The G- and A-ligands cleaved DNA at the AP site by promoting β-elimination in a non-selective manner by the G-ligand, and in a selective manner for the opposing dT by the A-ligand. These results suggest that the nucleobase-polyamine conjugate ligands may have the potential for enhancement of the cytotoxicities of the AP site.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yukiko S
authors.initials: YS
authors.lastname: Abe
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: sasaki@phar.kyushu-u.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry; D002330:Carmustine / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D053837:DNA Cleavage; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry*; D006868:Hydrolysis; D008024:Ligands; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs; D009711:Nucleotides / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008024:Ligands; D009711:Nucleotides; D011073:Polyamines; D011994:Recombinant Proteins; D004247:DNA; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D002330:Carmustine
keywords: AP site repair; APE1; Binding ligand; DNA cleavage; β-Elimination