Human DNA glycosylases involved in the repair of oxidatively damaged DNA
Human DNA glycosylases involved in the repair of oxidatively damaged DNA
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DOI：
10.1248/bpb.27.480
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发表时间：
2004-04-01
影响因子：
2
通讯作者：
Kotera, M
中科院分区：
文献类型：
--
作者：
Ide, H;Kotera, M
来自内源性和环境来源的活性氧引起DNA的氧化损伤，从而对细胞的遗传完整性构成巨大威胁。这种氧化性DNA损伤通过碱基切除修复（BER）途径恢复，该途径从细菌到人类都是保守的，并且由DNA糖基化酶启动，其通过水解N-糖苷键（单功能DNA糖基化酶）从DNA主链简单地去除异常碱基，或者进一步催化所得脱碱基位点的切割（双功能DNA糖基化酶）。在人类细胞中，氧化嘧啶损伤通常由hNTH 1、hNEIL 1或hNEIL 2去除，而氧化嘌呤损伤由hOGG 1去除。hSMUG 1切除了上述酶难以识别的氧化性碱基损伤的子集。与这些酶不同，hMYH在DNA复制过程中去除完整的错误掺入的相对模板8-氧代鸟嘌呤。虽然hNTH 1，hOGG 1和hMYH占主要的细胞糖基化酶活性的固有底物病变，小鼠模型缺乏的酶表现出没有明显的表型，如癌症的发展，这意味着备份机制。与小鼠模型相反，hMYH突变已被证明会导致多发性结直肠腺瘤综合征和高结直肠癌风险。对于N-糖苷键的裂解，双功能DNA糖基化酶（hNTH 1、hNEIL 1、hNEIL 2和hOGG 1）使用Lys或Pro直接攻击糖CV，而单功能DNA糖基化酶（hSMUG 1和hMYH）使用活化的水分子。氧化损伤的DNA糖基化酶，如果不是全部的话，被含有2-脱氧核糖内酯或恶嗪的DNA共价捕获。因此，使用共价捕获的功能性DNA糖基化酶的消耗可以降低癌细胞的BER能力，从而增强抗癌药物或放射疗法的功效。
Reactive oxygen species from endogenous and environmental sources induce oxidative damage to DNA, and hence pose an enormous threat to the genetic integrity of cells. Such oxidative DNA damage is restored by the base excision repair (BER) pathway that is conserved from bacteria to humans and is initiated by DNA glycosylases, which simply remove the aberrant base from the DNA backbone by hydrolyzing the N-glycosidic bond (monofunctional DNA glycosylase), or further catalyze the incision of a resulting abasic site (bifunctional DNA glycosylase). In human cells, oxidative pyrimidine lesions are generally removed by hNTH1, hNEIL1, or hNEIL2, whereas oxidative purine lesions are removed by hOGG1. hSMUG1 excises a subset of oxidative base damage that is poorly recognized by the above enzymes. Unlike these enzymes, hMYH removes intact A misincorporated opposite template 8-oxoguanine during DNA replication. Although hNTH1, hOGG1, and hMYH account for major cellular glycosylase activity for inherent substrate lesions, mouse models deficient in the enzymes exhibit no overt phenotypes such as the development of cancer, implying backup mechanisms. Contrary to the mouse model, hMYH mutations have been shown to lead to a multiple colorectal adenoma syndrome and high colorectal cancer risk. For cleavage of the N-glycosidic bond, bifunctional DNA glycosylases (hNTH1, hNEIL1, hNEIL2, and hOGG1) use Lys or Pro for direct attack on sugar CV, whereas monofunctional DNA glycosylases (hSMUG1 and hMYH) use an activated water molecule. DNA glycosylases for oxidative damage, if not all, are covalently trapped by DNA containing 2-deoxyribonolactone or oxanine. Thus, the depletion of functional DNA glycosylases using covalent trapping may reduce the BER capacity of cancer cells, hence potentiating the efficacy of anticancer drugs or radiation therapy.