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, À77T>C) in the XRCC1 gene 5 0 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 À77T>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 À77T>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 À77T>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 À77 genotypes (TC and CC) compared with the TT genotype (OR ¼ 1.46, 95% CI ¼ 1.18-1.82; P ¼ 0.001) and the increased risk was more pronounced in smokers (OR ¼ 1.63, 95% CI ¼ 1.20-2.21) than in non-smokers (OR ¼ 1.28, 95% CI ¼ 0.94-1.76). Taken together, these results showed that the functional SNP À77T>C in XRCC1 5 0 UTR was associated with cancer development owing to the decreased transcriptional activity of C-allelecontaining promoter with higher affinity to Sp1 binding.

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