DNA cleavage at the AP site via β-elimination mediated by the AP site-binding ligands
DNA cleavage at the AP site via β-elimination mediated by the AP site-binding ligands
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DOI：
10.1016/j.bmc.2016.01.016
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发表时间：
2016-02-15
影响因子：
3.5
通讯作者：
Sasaki, Shigeki
中科院分区：
文献类型：
--
作者：
Abe, Yukiko S.;Sasaki, Shigeki
DNA不断受到氧化和烷基化等内源性和外源性因素的损伤。在碱基切除修复途径中，受损的核碱基被DNA N-糖基化酶去除，形成脱碱基位点（AP位点）。烷基化抗肿瘤剂通过AP位点的形成而表现出细胞毒性。因此，AP位点修复途径的阻断或调节可增强DNA烷化剂的抗肿瘤功效。在这项研究中，我们研究了核碱基-多胺共轭配体（G-，A-，C-和T-配体）对AP位点切割的影响。G-配体和A-配体通过G-配体以非选择性方式促进β-消除并通过A-配体以选择性方式促进相对的dT，从而在AP位点切割DNA。这些结果表明，核碱基-多胺缀合物配体可能具有增强AP位点的细胞毒性的潜力。(C)2016爱思唯尔有限公司版权所有。
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 beta-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. (C) 2016 Elsevier Ltd. All rights reserved.