Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

Abstract

XPC, a key protein in the nucleotide excision repair (NER) pathway, recognizes damaged DNA and initiates NER. Genetic variations in the XPC gene might be associated with altered DNA repair capacities (DRC). In this study, we genotyped three XPC polymorphisms, Ala499Val (C → T), PAT (−/+) and Lys939Gln (A → C), and measured the DNA damage/DRC by alkaline comet assay challenged by BPDE and gamma-radiation in 476 healthy subjects. We also evaluated the associations between DNA damage/DRC and genotypes of XPC polymorphisms. Compared with the XPC Lys939Gln homozygous wild type (AA) subjects, subjects with the variant alleles (AC and CC) had significantly higher DNA damages induced by BPDE (Median and 95% confidence interval [CI]: 3.16 (3.01–3.44) vs. 2.88 (2.51–3.05), P = 0.01), and gamma-radiation (4.18 (3.94–4.44) vs. 3.71 (3.49–4.04), P = 0.01). However, subjects with the variant alleles (CT and TT) of Ala499Val exhibited a 8.6% and 13.1% decrease in DNA damages induced by BPDE ( P = 0.05) and gamma-radiation ( P = 0.001), respectively. Significant correlations were found between genotypes and induced DNA damages in XPC Lys939Gln (For BPDE: R = 0.12, P = 0.01; for gamma-radiation: R = 0.094, P = 0.046) and Ala499Val (For BPDE: R = −0.11, P = 0.03; for gamma-radiation: R = −0.16, P = 0.0009). The haplotypes “T-A” (in the order of Ala499Val-PAT-Lys939Gln) was associated with the lowest DNA damages. Our results suggested that the DRC of host cells might be modulated by specific XPC polymorphisms.