Repair of endogenous DNA damage
Repair of endogenous DNA damage
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DOI：
10.1101/sqb.2000.65.127
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发表时间：
2000-01-01
期刊：
影响因子：
--
通讯作者：
Barnes, DE
中科院分区：
文献类型：
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作者：
Lindahl, T;Barnes, DE
《冷泉港定量生物学研讨会》，卷LXV，© 2000冷泉港实验室出版社0-87969-605-2/00。7-甲基脱氧鸟苷残基的127胆汁糖基键。这种共同碱基损伤的产生和随后的丢失显著地促进了总DNA脱嘌呤速率，每天形成约3000个脱碱基位点。每个基因组约有4000个7-甲基鸟嘌呤残基的稳定状态明显出现（Rydberg and Lindahl 1982）。在正常的修复熟练的哺乳动物细胞，7-甲基鸟嘌呤是最有可能的主要异常碱基残基定期存在于DNA中，似乎不太可能，任何潜在的细胞毒性或promutagenic基地将被允许保持在这样的水平。修复缺陷型细菌的自发突变表型表明存在SAM以外的次要内源性甲基化剂（Wenik和Samson 1991）。这些试剂可能与甲基亚硝基脲更密切相关，诱导DNA中O 6-甲基鸟嘌呤和3-甲基腺嘌呤的形成，并可通过内源性代谢物的亚硝化产生（Taverna和Sedgwick 1996）。细菌和真核细胞具有特定的修复酶，可以从DNA中去除各种主要类型的氧化损伤。最常见的致突变碱基损伤8-羟基鸟嘌呤（8-oxoG）的DNA修复缺陷导致细菌和酵母菌中的强增突变表型（Michaels和米勒1992;托马斯et al. 1996）。这些数据表明，由活性氧物质产生的内源性DNA损伤的修复是相关的，在体内和显着的内源性氧化损伤DNA连续发生，可能在类似的水平，由于水解和内源性烷基化的损害。然而，与其他类型的内在DNA损伤相比，这种形式的DNA衰变的相对重要性仍然不清楚。这是因为相关活性氧物质的细胞内，特别是核内浓度尚未确定，而例如导致水解降解的水的细胞内浓度已知为55 M。损伤DNA的活性氧物质由铁介导的芬顿反应产生（Henle和Linn 1997），并且这种反应在细胞核中的频率尚不清楚。此外，在真核细胞中，大多数氧代谢已委托给线粒体，因此细胞核实际上是缺氧的（Joenje 1989）。然而，细胞核和细胞质中的脂质过氧化等过程明显相关，细胞应激可能增加DNA中形成的8-oxoG的量（Conlon等人，2000）。已经表征了由脂质过氧化副产物产生的环外DNA碱基加合物。其中最丰富的似乎是嘧啶嘌呤酮M1 G，它是通过DNA中的G残基与脂质过氧化产物丙二醛之间的反应产生的（Fink等人，1997年）。此外，脂质过氧化可产生丙烯醛和巴豆醛，它们容易代谢成环氧化物，可产生DNA碱基的环外乙烯基修饰。两个这样的碱基，乙烯基-A和乙烯基-C，被DNA糖基化酶有效地切除（Hang等人，1998年; Saparbaev和拉瓦尔1998），这强烈地表明，这种加合物的产生在体内以足够高的速率发生，从而危及基因组的稳定性。除了BER纠正的许多碱基改变之外。这类病变中特别令人感兴趣的是5，8-环嘌呤脱氧核苷（布鲁克斯等.
Cold Spring Harbor Symposia on Quantitative Biology, Volume LXV.© 2000 Cold Spring Harbor Laboratory Press 0-87969-605-2/00. 127 bile glycosyl bond of 7-methyldeoxyguanosine residues. The generation and subsequent loss of this common base lesion contribute significantly to the total DNA depurination rate with about 3000 abasic sites formed per day. A steady state of about 4000 7-methylguanine residues per genome apparently occurs (Rydberg and Lindahl 1982). In normal repair-proficient mammalian cells, 7-methylguanine is most likely the main aberrant base residue regularly present in DNA; it seems unlikely that any potentially cytotoxic or promutagenic base would be allowed to remain at such a level. The existence of minor endogenous methylating agents other than SAM has been indicated by spontaneous mutator phenotypes of repair-deficient bacteria (Rebeck and Samson 1991). These agents may be more closely related to methylnitrosourea, induce formation of both O6-methylguanine and 3-methyladenine in DNA, and can arise by nitrosation of endogenous metabolites (Taverna and Sedgwick 1996). Bacteria and eukaryotic cells have specific repair enzymes to remove the various major types of oxidative damage from DNA. A defect in DNA repair of the most common mutagenic base lesion, 8-hydroxyguanine (8-oxoG), leads to a strong mutator phenotype in bacteria and yeast (Michaels and Miller 1992; Thomas et al. 1996). These data show that repair of endogenous DNA damage generated by reactive oxygen species is relevant in vivo and that significant endogenous oxidative damage to DNA occurs continuously, perhaps at a similar level as damage due to hydrolysis and endogenous alkylation. However, the relative importance of this form of DNA decay remains unclear in comparison with other types of intrinsic DNA damage. This is because the intracellular, and especially intranuclear, concentrations of the relevant reactive oxygen species have not been determined, whereas the intracellular concentration of, for example, water that accounts for hydrolytic degradation is known to be 55 M. Reactive oxygen species that damage DNA are generated by iron-mediated Fenton reactions (Henle and Linn 1997), and the frequency of such reactions in the cell nucleus is not known. Furthermore, in eukaryotic cells, most oxygen metabolism has been delegated to mitochondria, so the cell nucleus is practically anoxic (Joenje 1989). Processes such as lipid peroxidation in the nucleus and cytoplasm are clearly relevant, however, and cellular stress may increase the amount of 8-oxoG formed in DNA (Conlon et al. 2000). Exocyclic DNA base adducts generated from lipid peroxidation by-products have been characterized. The most abundant of these appears to be the pyrimidopurinone M1G, which is generated by reaction between a G residue in DNA and the lipid peroxidation product, malondialdehyde (Fink et al. 1997). In addition, lipid peroxidation may yield acrolein and crotonaldehyde, which are readily metabolized to epoxides that can generate exocyclic etheno modifications of DNA bases. Two such bases, etheno-A and etheno-C, are excised efficiently by DNA glycosylases (Hang et al. 1998; Saparbaev and Laval 1998), which strongly suggests that generation of such adducts occurs at sufficiently high rates in vivo to endanger genomic stability.Oxygen free radicals generate small amounts of bulky DNA damage that require repair by the nucleotide excision repair pathway, in addition to the many base alterations corrected by BER. A particularly interesting lesion of this class is the 5, 8-cyclopurine deoxynucleoside (Brooks et al …