title: A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer.
abstract: X-ray repair cross-complementing 1 (XRCC1) plays a key role in DNA base excision repair and cells lacking its activity are hypersensitive to DNA damage. Recently, we reported a SNP (rs3213245, -77T>C) in the XRCC1 gene 5' untranslated region (UTR) was significantly associated with the risk of developing esophageal squamous-cell carcinoma. Computer analysis predicted that this SNP was in the core of Sp1-binding motif, which suggested its functional significance. Gel shift and super shift assays confirmed that -77T>C polymorphic site in the XRCC1 promoter was within the Sp1-binding motif and the T>C substitution greatly enhanced the binding affinity of Sp1 to this region. Luciferase assays indicated that the Sp1-high-affinity C-allelic XRCC1 promoter was associated with a reduced transcriptional activity. The association between -77T>C and three other amino-acid substitution-causing polymorphisms in XRCC1 and risk of lung cancer was examined in 1024 patients and 1118 controls and the results showed that only the -77T>C polymorphism was significantly associated with an increased risk of developing lung cancer. Multivariate logistic regression analysis found that an increased risk of lung cancer was associated with the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR=1.46, 95% CI=1.18-1.82; P=0.001) and the increased risk was more pronounced in smokers (OR=1.63, 95% CI=1.20-2.21) than in non-smokers (OR=1.28, 95% CI=0.94-1.76). Taken together, these results showed that the functional SNP -77T>C in XRCC1 5'UTR was associated with cancer development owing to the decreased transcriptional activity of C-allele-containing promoter with higher affinity to Sp1 binding.
authors.affiliation: Department of Biology Sciences and Biotechnology, Tsinghua University, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Hao
authors.forename: X
authors.initials: X
authors.lastname: Miao
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Sun
authors.forename: G
authors.initials: G
authors.lastname: Liang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Tan
authors.forename: Q
authors.initials: Q
authors.lastname: Wei
authors.forename: D
authors.initials: D
authors.lastname: Lin
authors.forename: F
authors.initials: F
authors.lastname: He
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human