title: The ERCC2/XPD Lys751Gln polymorphism affects DNA repair of benzo[a]pyrene induced damage, tested in an in vitro model.
abstract: 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.
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Sha
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Dept. of Thoracic Surgery Ward 2, The first Hospital of China Medical University, Shenyang, PR China.
authors.forename: Su
authors.initials: S
authors.lastname: Cui
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China. Electronic address: xiaobo-lu@163.com.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Lu
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Li
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Jin
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Shengwen
authors.initials: S
authors.lastname: Wu
authors.affiliation: Dept. Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D016466:CHO Cells; D002273:Carcinogens / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D003412:Cricetulus; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D011110:Polymorphism, Genetic; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D002273:Carcinogens; D001564:Benzo(a)pyrene; D051759:Xeroderma Pigmentosum Group D Protein
keywords: Benzo[a]pyrene (B[a]P); Cancer development; DNA repair capacity; ERCC2/XPD Lys751Gln; Nucleotide excision repair (NER)