Action of multiple base excision repair enzymes on the 2′-deoxyribonolactone
Action of multiple base excision repair enzymes on the 2′-deoxyribonolactone
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DOI：
10.1016/j.bbrc.2005.01.082
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发表时间：
2005-03-25
影响因子：
3.1
通讯作者：
Constant, JF
中科院分区：
文献类型：
--
作者：
Faure, V;Saparbaev, M;Constant, JF
自由基对糖-磷酸骨架的攻击会在DNA中产生氧化的无嘌呤/脱嘧啶(AP)残基。2‘-脱氧核糖内酯(c[L])是由紫外线、伽马射线和某些抗癌药物引起的氯氧化AP位点损伤。如果不修复，dL会在大肠杆菌中产生G-->；A转换。在碱基切除修复(BER)途径中，AP内切酶是负责5‘切开正常AP位点(DR)和dL的主要酶。具有相关AP裂解酶活性的DNA糖基酶也可以有效地切割规则的AP位点。在这里，我们报告dL是AP内切酶的底物，但不是DNA糖基酶/AP裂解酶的底物。C[L]切口组的动力学参数与DR组相似。DNA糖基化酶，如大肠杆菌形成烟肼并嘧啶-DNA糖基酶、错配特异性尿嘧啶-DNA糖基酶和人烷基嘌呤-DNA N-糖基酶与dL强烈结合而不切割它。我们发现dL与人类蛋白质8-氧鸟嘌呤-DNA(HOGG1)和胸腺嘧啶二醇-DNA糖基酶(HNth1)发生交联，DR与Nth和hNth1发生交联。这些结果提示，dL和DR的遗传毒性可能通过BER途径在体内得到加强。(C)2005 Elsevier Inc.保留所有权利。
Free radical attack on the sugar-phosphate backbone generates oxidized apurinic/apyrimidinic (AP) residues in DNA. 2'-deoxyribonolactone (c[L) is a Cl'-oxidized AP site damage generated by UV and gamma-irradiation, and certain anticancer drugs. If not repaired dL produces G --> A transitions in Escherichia coli. In the base excision repair (BER) pathway, AP endonucleases are the major enzymes responsible for 5'-incision of the regular AP site (dR) and dL. DNA glycosylases with associated AP lyase activity can also efficiently cleave regular AP sites. Here, we report that dL is a substrate for AP endonucleases but not for DNA glycosylases/AP lyases. The kinetic parameters of the c[L-incision were similar to those of the dR. DNA glycosylases such as E coli formarniclopyrinlidine-DNA glycosylase, mismatch-specific Uracil-DNA glycosylase, and human alkylpurine-DNA N-glycosylase bind strongly to dL Without cleaving it. We show that dL cross-links with the human proteins 8-oxoguanine-DNA (hOGG1) and thymine glycol-DNA glycosylases (hNth1), and dR cross-links with Nth and hNth1. These results suggest that dL and dR induced genotoxicity might be strengthened by BER pathway in vivo. (C) 2005 Elsevier Inc. All rights reserved.