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标题：Human DNA Glycosylases Involved in the Repair of Oxidatively Damaged DNA
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作者：Hiroshi Ide ; Mitsuharu Kotera
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2004
卷号：27
期号：4
页码：480-485
DOI：10.1248/bpb.27.480
出版社：The Pharmaceutical Society of Japan
摘要：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 C1′, 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.
关键词：oxidative DNA damage;DNA glycosylase;action mechanism;covalent trapping;anticancer drug development