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Repair-Resistant DNA Lesions
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2017-08-10 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00128
Nicholas E. Geacintov 1 , Suse Broyde 1
Affiliation  

The eukaryotic global genomic nucleotide excision repair (GG-NER) pathway is the major mechanism that removes most bulky and some nonbulky lesions from cellular DNA. There is growing evidence that certain DNA lesions are repaired slowly or are entirely resistant to repair in cells, tissues, and in cell extract model assay systems. It is well established that the eukaryotic DNA lesion-sensing proteins do not detect the damaged nucleotide, but recognize the distortions/destabilizations in the native DNA structure caused by the damaged nucleotides. In this article, the nature of the structural features of certain bulky DNA lesions that render them resistant to NER, or cause them to be repaired slowly, is compared to that of those that are good-to-excellent NER substrates. Understanding the structural features that distinguish NER-resistant DNA lesions from good NER substrates may be useful for interpreting the biological significance of biomarkers of exposure of human populations to genotoxic environmental chemicals. NER-resistant lesions can survive to replication and cause mutations that can initiate cancer and other diseases. Furthermore, NER diminishes the efficacy of certain chemotherapeutic drugs, and the design of more potent pharmaceuticals that resist repair can be advanced through a better understanding of the structural properties of DNA lesions that engender repair-resistance.

中文翻译:

修复抗性DNA损伤

真核生物全球基因组核苷酸切除修复(GG-NER)途径是从细胞DNA去除大部分大块和部分非大块病变的主要机制。越来越多的证据表明某些DNA损伤在细胞,组织和细胞提取物模型测定系统中修复缓慢或完全抗修复。公认的是,真核DNA损伤感测蛋白不能检测到受损的核苷酸,但是可以识别由受损的核苷酸引起的天然DNA结构的变形/去稳定化。在本文中,将某些体积较大的DNA损伤的结构特征的性质(与使它们成为NER底物的优良特征)进行了比较,这些损伤使它们对NER产生抗性,或导致它们被缓慢修复。理解将耐NER的DNA损伤与良好的NER底物区分开的结构特征可能有助于解释人类人群暴露于遗传毒性环境化学物质中的生物标志物的生物学意义。耐NER的病灶可以存活并复制,并引起可引发癌症和其他疾病的突变。此外,NER会降低某些化学治疗药物的功效,并且可以通过更好地理解产生修复抵抗力的DNA损伤的结构特性,来设计出更强效的抗修复药物。耐NER的病灶可以存活并复制,并引起可引发癌症和其他疾病的突变。此外,NER会降低某些化学治疗药物的功效,并且可以通过更好地理解产生修复抵抗力的DNA损伤的结构特性,来设计出更强效的抗修复药物。耐NER的病灶可以存活并复制,并引起可引发癌症和其他疾病的突变。此外,NER会降低某些化学治疗药物的功效,并且可以通过更好地理解产生修复抵抗力的DNA损伤的结构特性,来设计出更强效的抗修复药物。
更新日期:2017-08-10
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