Oxidative DNA damage repair in mammalian cells: A new perspective
Oxidative DNA damage repair in mammalian cells: A new perspective
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DOI：
10.1016/j.dnarep.2006.10.011
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发表时间：
2007-04-01
期刊：
影响因子：
3.8
通讯作者：
Roy, Rabindra
中科院分区：
文献类型：
--
作者：
Hazra, Tapas K.;Das, Aditi;Roy, Rabindra
氧化诱导的DNA损伤与许多疾病（包括癌症）和衰老的病因学有关。所有生物体中氧化损伤碱基的修复主要通过DNA碱基切除修复（BER）途径发生，起始于DNA糖基化酶对其的切除。只有两种哺乳动物DNA糖基化酶，即大肠杆菌OGG 1和NTH 1。大肠杆菌Nth家族，以前的特点，切除大部分的氧化损伤的基础病变。我们最近发现并表征了E. coliNei中发现了第二个氧化碱基特异性糖基化酶家族的原型，并将其命名为NEIL（Nei-like）-1和2。NEIL在结构特征和反应机制上与NTH 1和OGG 1不同，但作用于许多相同的底物。N型DNA糖基化酶在碱基切除后，在所得AP位点切割DNA链以产生3 '-α β不饱和醛，而Nei型酶产生T-磷酸末端。E.大肠杆菌APE除了切割AP位点以产生3 '-OH（用于后续DNA修复合成的引物末端）之外，还有效地去除两种类型的末端。相反，哺乳动物APE，APE 1，在NTH 1/OGG 1引发的BER中具有重要作用，具有可忽略的T-磷酸酶活性，并且对于NEIL引发的BER是无效的。多核苷酸激酶（PNK）存在于哺乳动物细胞中，而不存在于大肠杆菌中。大肠杆菌，去除3'磷酸，并参与NEIL启动的BER。NEIL显示出从DNA泡中切除病变的独特偏好，而大多数DNA糖基化酶，包括OGG 1和NTH 1，仅对双链DNA有活性。NEIL和NTH 1/OGG 1对气泡与双链体DNA底物的偏好的二分法表明，NEIL在复制和/或转录期间优先修复碱基损伤，因此在维持哺乳动物基因组的功能完整性方面发挥独特作用。(c)2006 Elsevier B. V.保留所有权利。
Oxidatively induced DNA lesions have been implicated in the etiology of many diseases (including cancer) and in aging. Repair of oxidatively damaged bases in all organisms occurs primarily via the DNA base excision repair (BER) pathway, initiated with their excision by DNA glycosylases. Only two mammalian DNA glycosylases, OGG1 and NTH1 of E. coli Nth family, were previously characterized, which excise majority of the oxidatively damaged base lesions. We recently discovered and characterized two human orthologs of E. coli Nei, the prototype of the second family of oxidized base-specific glycosylases and named them NEIL (Nei-like)-1 and 2. NEILs are distinct from NTH1 and OGG1 in structural features and reaction mechanism but act on many of the same substrates. Nth-type DNA glycosylases after base excision, cleave the DNA strand at the resulting AP-site to produce a 3'-alpha beta unsaturated aldehyde whereas Nei-type enzymes produce T-phosphate terminus. E. coli APEs efficiently remove both types of termini in addition to cleaving AP sites to generate 3'-OH, the primer terminus for subsequent DNA repair synthesis. in contrast, the mammalian APE, APE1, which has an essential role in NTH1/OGG1-initiated BER, has negligible T-phosphatase activity and is dispensable for NEIL-initiated BER. Polynucleotide kinase (PNK), present in mammalian cells but not in E. coli, removes the 3' phosphate, and is involved in NEIL-initiated BER. NEILs show a unique preference for excising lesions from a DNA bubble, while most DNA glycosylases, including OGG1 and NTH1, are active only with duplex DNA. The dichotomy in the preference of NEILs and NTH1/OGG1 for bubble versus duplex DNA substrates suggests that NEILs function preferentially in repair of base lesions during replication and/or transcription and hence play a unique role in maintaining the functional integrity of mammalian genomes. (c) 2006 Elsevier B.V. All rights reserved.