National Laboratory Astana, Nazarbayev University, Astana, Kazakhstan.
Groupe «Réparation de l'ADN», Equipe Labellisée par la Ligue Nationale Contre le Cancer, CNRS UMR8200, Université Paris-Sud, Villejuif Cedex, France.
Adv Exp Med Biol. 2020;1241:77-100. doi: 10.1007/978-3-030-41283-8_6.
A variety of endogenous and exogenous factors induce chemical and structural alterations in cellular DNA in addition to the errors occurring throughout DNA synthesis. These types of DNA damage are cytotoxic, miscoding or both and are believed to be at the origin of cancer and other age-related diseases. A human cell, aside from nuclear DNA, contains thousands of copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It has been proposed that mtDNA is a critical target of reactive oxygen species: by-products of oxidative phosphorylation that are generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA is more extensive and persistent as compared to that to nuclear DNA. Although transversions are the hallmark of mutations induced by reactive oxygen species, paradoxically, the majority of mtDNA mutations that occur during ageing and cancer are transitions. Furthermore, these mutations show a striking strand orientation bias: T→C/G→A transitions preferentially occur on the light strand, whereas C→T/A→G on the heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the heavy strand only, owing to asymmetric replication of the DNA strand anchored to the inner membrane via the D-loop structure.
除了在整个 DNA 合成过程中发生的错误之外，各种内源性和外源性因素还会导致细胞 DNA 的化学和结构改变。这些类型的 DNA 损伤具有细胞毒性、编码错误或两者兼而有之，被认为是癌症和其他与年龄相关疾病的根源。人类细胞除了核 DNA 之外，还含有数千份线粒体 DNA（mtDNA），mtDNA 是一种双链、环状分子，大小为 16569bp。有人提出，mtDNA 是活性氧（ROS）的一个关键靶点：ROS 是有氧呼吸过程中细胞器中产生的氧化磷酸化的副产物。事实上，与核 DNA 相比，mtDNA 的氧化损伤更广泛且更持久。尽管颠换是由活性氧诱导的突变的标志，但具有讽刺意味的是，衰老和癌症过程中发生的大多数 mtDNA 突变都是转换。此外，这些突变表现出明显的链取向偏倚：T→C/G→A 转换优先发生在线粒体 DNA 的轻链上，而 C→T/A→G 则发生在线粒体 DNA 的重链上。在这里，我们提出，由于通过 D 环结构固定在内膜上的 DNA 链的不对称复制，在多次 DNA 复制后产生的大多数 mtDNA 后代仅源自重链。
