The ERCC2/XPD Lys751Gln polymorphism affects DNA repair of benzo[a]pyrene induced damage, tested in an in vitro model.
The ERCC2/XPD Lys751Gln polymorphism affects DNA repair of benzo[a]pyrene induced damage, tested in an in vitro model.
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DOI：
10.1016/j.tiv.2016.04.015
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发表时间：
2016-08
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影响因子：
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通讯作者：
Sha Xiao;S. Cui;Xiaobo Lu;Yangyang Guan;Dandan Li;Qiu-fang Liu;Yuan Cai;Cuihong Jin;Jinghua Yang;Sheng-wen Wu;T. van der Straaten
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文献类型：
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作者：
Sha Xiao;S. Cui;Xiaobo Lu;Yangyang Guan;Dandan Li;Qiu-fang Liu;Yuan Cai;Cuihong Jin;Jinghua Yang;Sheng-wen Wu;T. van der Straaten
核苷酸切除修复（NER）是机体对苯并[a]芘（B[a]P）等外源性致癌物和诱变剂的一种重要防御机制。ERCC 2/XPD基因多态性是NER的一个关键因素，被认为与个体的癌症易感性有关。尽管ERCC 2/XPD Lys 751 Gln（rs 13181）是研究最多的多态性，但该多态性对致癌物DNA修复能力的影响仍不清楚。在本研究中，携带不同基因型的ERCC 2/XPD（Lys 751 Gln）的cDNA克隆导入ERCC 2/XPD缺陷细胞系（UV 5）中，在良好控制的生物系统中。B[a]P处理后，分别检测细胞生长抑制率和DNA损伤水平。正如预期的那样，我们发现在导入ERCC 2/XPD的cDNA克隆（Lys 751）后，UV 5细胞中的DNA修复能力恢复到与野生型亲本AA 8细胞相似的水平。有趣的是，在B[a]P处理后，表达变体ERCC 2/XPD（751 Gln）的转染细胞显示出增强的细胞敏感性和降低的DNA修复能力。野生型基因型AA（赖氨酸）被发现与较高的DNA修复能力相比，其多态性基因型CC（谷氨酰胺）。这些数据表明，ERCC 2/XPD Lys 751 Gln多态性影响DNA修复能力后，暴露于环境致癌物，如B[a]P在这个良好控制的体外系统，并可以作为一个生物标志物，以增加发展癌症的预测价值。
Nucleotide excision repair (NER) is an important defense mechanism of the body to exogenous carcinogens and mutagens, such as benzo[a]pyrene (B[a]P). Genetic polymorphisms in ERCC2/XPD, a critical element in NER, are thought to be associated with individual's cancer susceptibility. Although ERCC2/XPD Lys751Gln (rs13181) is the most studied polymorphism, the impact of this polymorphism on DNA repair capacity to carcinogen remains unclear. In the present study, cDNA clones carrying different genotypes of ERCC2/XPD (Lys751Gln) were introduced into an ERCC2/XPD deficient cell line (UV5) in a well-controlled biological system. After B[a]P treatment, cell growth inhibition rates and DNA damage levels in all cells were detected respectively. As expected, we found that the DNA repair capacity in UV5 cells was restored to levels similar to wildtype parent AA8 cells upon introduction of the cDNA clone of ERCC2/XPD (Lys751). Interestingly, after B[a]P treatment, transfected cells expressing variant ERCC2/XPD (751Gln) showed an enhanced cellular sensitivity and a diminished DNA repair capacity. The wildtype genotype AA (Lys) was found to be associated with a higher DNA repair capacity as compared to its polymorphic genotype CC (Gln). These data indicate that ERCC2/XPD Lys751Gln polymorphism affects DNA repair capacity after exposure to environmental carcinogens such as B[a]P in this well-controlled in vitro system and could act as a biomarker to increase the predictive value to develop cancer.