Pre-Replicative Repair of Oxidized Bases Maintains Fidelity in Mammalian Genomes: The Cowcatcher Role of NEIL1 DNA Glycosylase.
Pre-Replicative Repair of Oxidized Bases Maintains Fidelity in Mammalian Genomes: The Cowcatcher Role of NEIL1 DNA Glycosylase.
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DOI：
10.3390/genes8070175
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发表时间：
2017-06-30
期刊：
影响因子：
3.5
通讯作者：
Hegde ML
中科院分区：
文献类型：
--
作者：
Rangaswamy S;Pandey A;Mitra S;Hegde ML
人类基因组的保真度不断受到代谢过程中内源性和外源性物质产生的基因毒性活性氧（ROS）的挑战。在DNA复制过程中，大多数ros诱导的氧化碱基损伤的错配对诱导突变。虽然由紫外光和其他环境诱变剂诱导的大体积碱基加合物会阻断复制性DNA聚合酶，但大多数氧化碱基损伤不会阻断DNA合成。在8-oxo-G中：由相反的未修复的8-oxo-G结合而产生的错配，A被MutYH （MYH）去除进行复制后修复，其他氧化的碱基损伤必须在复制前修复，以防止突变固定。我们早期的研究记录了哺乳动物细胞中五种氧化碱基切除修复（BER）启动酶之一的内切酶VIII-like 1 (NEIL1) DNA糖基酶（DG）的S期特异性过表达，以及它对复制叉模拟单链DNA底物的高亲和力。我们最近为NEIL1在复制链修复中的作用提供了实验证据，并提出了复制前BER的“cowcatcher”模型，其中NEIL1与ssDNA模板中病变碱基的非生产力结合阻断了DNA链的延伸，导致分叉回归。损伤的修复是由NEIL1与DNA复制蛋白联合进行的。在这篇评论中，我们强调了复制前BER在预防突变中的关键作用，并讨论了复制前BER和复制后BER的区别。
Genomic fidelity in the humans is continuously challenged by genotoxic reactive oxygen species (ROS) generated both endogenously during metabolic processes, and by exogenous agents. Mispairing of most ROS-induced oxidized base lesions during DNA replication induces mutations. Although bulky base adducts induced by ultraviolet light and other environmental mutagens block replicative DNA polymerases, most oxidized base lesions do not block DNA synthesis. In 8-oxo-G:A mispairs generated by the incorporation of A opposite unrepaired 8-oxo-G, A is removed by MutYH (MYH) for post-replicative repair, and other oxidized base lesions must be repaired prior to replication in order to prevent mutation fixation. Our earlier studies documented S phase-specific overexpression of endonuclease VIII-like 1 (NEIL1) DNA glycosylase (DG), one of five oxidized base excision repair (BER)-initiating enzymes in mammalian cells, and its high affinity for replication fork-mimicking single-stranded (ss)DNA substrates. We recently provided experimental evidence for the role of NEIL1 in replicating-strand repair, and proposed the “cowcatcher” model of pre-replicative BER, where NEIL1’s nonproductive binding to the lesion base in ssDNA template blocks DNA chain elongation, causing fork regression. Repair of the lesion in the then re-annealed duplex is carried out by NEIL1 in association with the DNA replication proteins. In this commentary, we highlight the critical role of pre-replicative BER in preventing mutagenesis, and discuss the distinction between pre-replicative vs. post-replicative BER.
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作者：
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DOI：
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