Chemical and enzymatic modifications of 5-methylcytosine at the intersection of DNA damage, repair, and epigenetic reprogramming.
Chemical and enzymatic modifications of 5-methylcytosine at the intersection of DNA damage, repair, and epigenetic reprogramming.
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DOI：
10.1371/journal.pone.0273509
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
所有生物体的DNA都受到内源性反应（包括脱氨和氧化）的持续破坏。这种损伤，如果没有正确修复，可能会导致突变，驱动肿瘤的发展。除了化学损伤，最近的研究已经确定，DNA碱基可以被酶修饰，产生许多相同的修饰碱基。无论形成机制如何，修饰的碱基都可以改变DNA-蛋白质相互作用，从而调节基因转录的表观遗传控制。DNA中同时存在化学和酶修饰的碱基表明DNA修复和表观遗传重编程之间存在潜在的交叉或碰撞。在本文中，我们已经准备好了定义的序列寡核苷酸包含一套完整的氧化和脱氨基的碱基，可能会出现从5-甲基胞嘧啶。我们已经探测了这些底物与人类糖基化酶参与DNA修复和表观遗传重编程。本文报道的新观察结果包括：当与A或G配对时，SMUG 1切除5-羧基尿嘧啶（5caU）。TDG和MBD 4在与G错配时都能切割5-甲酰尿嘧啶和5caU。此外，TDG不仅在与G配对时去除5-甲酰基胞嘧啶和5-羧基胞嘧啶，而且在与A错配时也去除5-甲酰基胞嘧啶和5-羧基胞嘧啶。令人惊讶的是，5caU是人TDG、SMUG 1和MBD 4的最佳底物之一，并且比T.这里提供的数据介绍了一些意想不到的发现，对内源性DNA损伤，修复和表观遗传重编程途径之间的相互作用提出了新的问题。
The DNA of all living organisms is persistently damaged by endogenous reactions including deamination and oxidation. Such damage, if not repaired correctly, can result in mutations that drive tumor development. In addition to chemical damage, recent studies have established that DNA bases can be enzymatically modified, generating many of the same modified bases. Irrespective of the mechanism of formation, modified bases can alter DNA-protein interactions and therefore modulate epigenetic control of gene transcription. The simultaneous presence of both chemically and enzymatically modified bases in DNA suggests a potential intersection, or collision, between DNA repair and epigenetic reprogramming. In this paper, we have prepared defined sequence oligonucleotides containing the complete set of oxidized and deaminated bases that could arise from 5-methylcytosine. We have probed these substrates with human glycosylases implicated in DNA repair and epigenetic reprogramming. New observations reported here include: SMUG1 excises 5-carboxyuracil (5caU) when paired with A or G. Both TDG and MBD4 cleave 5-formyluracil and 5caU when mispaired with G. Further, TDG not only removes 5-formylcytosine and 5-carboxycytosine when paired with G, but also when mispaired with A. Surprisingly, 5caU is one of the best substrates for human TDG, SMUG1 and MBD4, and a much better substrate than T. The data presented here introduces some unexpected findings that pose new questions on the interactions between endogenous DNA damage, repair, and epigenetic reprogramming pathways.
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