DNA cleavage at the AP site via β-elimination mediated by the AP site-binding ligands |
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| Institution: | 1. The Key Laboratory of Beam Technology and Material Modification of the Ministry of Education, College of Nuclear Science and Technology, Beijing Normal University, Beijing 100875, China;2. Beijing Radiation Center, Beijing 100875, China;3. Center of Theoretical Nuclear Physics, National Laboratory of the Heavy Ion Accelerator of Lanzhou, Lanzhou 730000, China;1. Department of Genetics and Biochemistry, Clemson University, Room 049 Life Sciences Facility, 190 Collings Street, Clemson, SC 29634, USA;2. Department of Biological Sciences, The University at Albany, SUNY, 1400 Washington Avenue, Albany, NY 12222, USA;1. Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan;2. Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0373, Japan;3. Biological Science and Technology, Tokyo University of Science, 6-1-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan;4. Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan;1. Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA;2. Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA;3. Department of Microbiology, NYU Langone Medical Center, New York, NY 10016, USA;4. Infectious Disease Laboratory, Salk Institute, La Jolla, CA 92037, USA |
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| 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. |
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| Keywords: | AP site repair β-Elimination Binding ligand DNA cleavage APE1 |
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