Rangaswamy Suganya, Pandey Arvind, Mitra Sankar, Hegde Muralidhar L
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Genes (Basel). 2017 Jun 30;8(7):175. doi: 10.3390/genes8070175.
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.
人类基因组的保真度不断受到基因毒性活性氧（ROS）的挑战，这些活性氧既在代谢过程中内源性产生，也由外源性因素产生。DNA复制过程中大多数由ROS诱导的氧化碱基损伤错配会导致突变。尽管紫外线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。在未修复的8-氧代鸟嘌呤（8-oxo-G）对面掺入腺嘌呤（A）产生的8-氧代鸟嘌呤：腺嘌呤（8-oxo-G:A）错配中，A会被MutYH（MYH）去除以进行复制后修复，其他氧化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核酸内切酶VIII样1（NEIL1）DNA糖基化酶（DG）在S期特异性过表达，它是哺乳动物细胞中五种氧化碱基切除修复（BER）起始酶之一，并且对模拟复制叉的单链（ss）DNA底物具有高亲和力。我们最近提供了实验证据证明NEIL1在复制链修复中的作用，并提出了复制前BER的“捕牛器”模型，即NEIL1与ssDNA模板中的损伤碱基非生产性结合会阻断DNA链延伸，导致叉状结构倒退。然后由NEIL1与DNA复制蛋白协同对重新退火的双链中的损伤进行修复。在这篇评论中，我们强调了复制前BER在防止诱变中的关键作用，并讨论了复制前BER与复制后BER之间的区别。
