Bohr Vilhelm A, Stevnsner Tinna, de Souza-Pinto Nadja C
Laboratory of Molecular Gerontology, Box 1, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Gene. 2002 Mar 6;286(1):127-34. doi: 10.1016/s0378-1119(01)00813-7.
Nuclear and mitochondrial DNA are constantly being exposed to damaging agents, from endogenous and exogenous sources. In particular, reactive oxygen species (ROS) are formed at high levels as by-products of the normal metabolism. Upon oxidative attack of DNA many DNA lesions are formed and oxidized bases are generated with high frequency. Mitochondrial DNA has been shown to accumulate high levels of 8-hydroxy-2'-deoxyguanosine, the product of hydroxylation of guanine at carbon 8, which is a mutagenic lesion. Most of these small base modifications are repaired by the base excision repair (BER) pathway. Despite the initial concept that mitochondria lack DNA repair, experimental evidences now show that mitochondria are very proficient in BER of oxidative DNA damage, and proteins necessary for this pathway have been isolated from mammalian mitochondria. Here, we examine the BER pathway with an emphasis on mtDNA repair. The molecular mechanisms involved in the formation and removal of oxidative damage from mitochondria are discussed. The pivotal role of the OGG1 glycosylase in removal of oxidized guanines from mtDNA will also be examined. Lastly, changes in mtDNA repair during the aging process and possible biological implications are discussed.
核DNA和线粒体DNA不断受到来自内源性和外源性的损伤因子影响。特别是，作为正常新陈代谢的副产物，活性氧（ROS）会大量生成。DNA受到氧化攻击后会形成许多DNA损伤，并高频产生氧化碱基。线粒体DNA已被证明会积累高水平的8-羟基-2'-脱氧鸟苷，它是鸟嘌呤在碳8位羟基化的产物，是一种诱变损伤。这些小的碱基修饰大多通过碱基切除修复（BER）途径进行修复。尽管最初认为线粒体缺乏DNA修复能力，但现在实验证据表明，线粒体在氧化DNA损伤的BER方面非常高效，并且该途径所需的蛋白质已从哺乳动物线粒体中分离出来。在这里，我们重点研究线粒体DNA修复的BER途径。讨论了线粒体中氧化损伤形成和去除所涉及的分子机制。还将研究OGG1糖基化酶在从线粒体DNA中去除氧化鸟嘌呤方面的关键作用。最后，讨论了衰老过程中线粒体DNA修复的变化及其可能的生物学意义。
