Talhaoui Ibtissam, Matkarimov Bakhyt T, Tchenio Thierry, Zharkov Dmitry O, Saparbaev Murat K
Groupe «Réparation de l'ADN», Equipe Labellisée par la Ligue Nationale Contre le Cancer, CNRS UMR8200, Université Paris-Sud, Gustave Roussy Cancer Campus, F-94805 Villejuif Cedex, France.
National laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan.
Free Radic Biol Med. 2017 Jun;107:266-277. doi: 10.1016/j.freeradbiomed.2016.11.040. Epub 2016 Nov 24.
In cellular organisms composition of DNA is constrained to only four nucleobases A, G, T and C, except for minor DNA base modifications such as methylation which serves for defence against foreign DNA or gene expression regulation. Interestingly, this severe evolutionary constraint among other things demands DNA repair systems to discriminate between regular and modified bases. DNA glycosylases specifically recognize and excise damaged bases among vast majority of regular bases in the base excision repair (BER) pathway. However, the mismatched base pairs in DNA can occur from a spontaneous conversion of 5-methylcytosine to thymine and DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved special DNA repair systems that target the non-damaged DNA strand in a duplex to remove mismatched regular DNA bases. Mismatch-specific adenine- and thymine-DNA glycosylases (MutY/MUTYH and TDG/MBD4, respectively) initiated BER and mismatch repair (MMR) pathways can recognize and remove normal DNA bases in mismatched DNA duplexes. Importantly, in DNA repair deficient cells bacterial MutY, human TDG and mammalian MMR can act in the aberrant manner: MutY and TDG removes adenine and thymine opposite misincorporated 8-oxoguanine and damaged adenine, respectively, whereas MMR removes thymine opposite to O-methylguanine. These unusual activities lead either to mutations or futile DNA repair, thus indicating that the DNA repair pathways which target non-damaged DNA strand can act in aberrant manner and introduce genome instability in the presence of unrepaired DNA lesions. Evidences accumulated showing that in addition to the accumulation of oxidatively damaged DNA in cells, the aberrant DNA repair can also contribute to cancer, brain disorders and premature senescence. For example, the aberrant BER and MMR pathways for oxidized guanine residues can lead to trinucleotide expansion that underlies Huntington's disease, a severe hereditary neurodegenerative syndrome. This review summarises the present knowledge about the aberrant DNA repair pathways for oxidized base modifications and their possible role in age-related diseases.
在细胞生物中，DNA的组成仅限于四种核碱基A、G、T和C，除了一些微小的DNA碱基修饰，如用于抵御外来DNA或基因表达调控的甲基化。有趣的是，这种严格的进化限制要求DNA修复系统区分正常碱基和修饰碱基。DNA糖基化酶在碱基切除修复（BER）途径中，能在绝大多数正常碱基中特异性识别并切除受损碱基。然而，DNA中的错配碱基对可能源于5-甲基胞嘧啶自发转化为胸腺嘧啶以及复制过程中DNA聚合酶的错误。为了应对这些对基因组稳定性的诱变威胁，细胞进化出了特殊的DNA修复系统，该系统以双链中非受损的DNA链为靶点，去除错配的正常DNA碱基。错配特异性腺嘌呤和胸腺嘧啶DNA糖基化酶（分别为MutY/MUTYH和TDG/MBD4）启动的BER和错配修复（MMR）途径，能够识别并去除错配DNA双链中的正常DNA碱基。重要的是，在DNA修复缺陷的细胞中，细菌的MutY、人类的TDG和哺乳动物的MMR会以异常的方式起作用：MutY和TDG分别去除与错误掺入的8-氧鸟嘌呤和受损腺嘌呤相对的腺嘌呤和胸腺嘧啶，而MMR则去除与O-甲基鸟嘌呤相对的胸腺嘧啶。这些异常活动要么导致突变，要么导致无效的DNA修复，从而表明以非受损DNA链为靶点的DNA修复途径在存在未修复的DNA损伤时，可能以异常方式起作用并引入基因组不稳定性。越来越多的证据表明，除了细胞中氧化损伤DNA的积累外，异常的DNA修复也可能导致癌症、脑部疾病和早衰。例如，针对氧化鸟嘌呤残基的异常BER和MMR途径可导致三核苷酸扩增，这是亨廷顿舞蹈病（一种严重的遗传性神经退行性综合征）的基础。本综述总结了目前关于氧化碱基修饰的异常DNA修复途径及其在与年龄相关疾病中可能作用的知识。
