XPD polymorphisms: effects on DNA repair proficiency

Abstract

XPD codes for a DNA helicase involved in transcription and nucleotide excision repair. Rare XPD mutations diminish nucleotide excision repair resulting in hypersensitivity to UV light and increased risk of skin cancer. Several polymorphisms in this gene have been identified but their impact on DNA repair is not known. We compared XPD genotypes at codons 312 and 751 with DNA repair proficiency in 31 women. XPD genotypes were measured by PCR-RFLP. DNA repair proficiency was assessed using a cytogenetic assay that detects X-ray induced chromatid aberrations (breaks and gaps). Chromatid aberrations were scored per 100 metaphase cells following incubation at 37 degrees C (1.5 h after irradiation) to allow for repair of DNA damage. Individuals with the Lys/Lys codon 751 XPD genotype had a higher number of chromatid aberrations (132/100 metaphase cells) than those having a 751Gln allele (34/100 metaphase cells). Individuals having greater than 60 chromatid breaks plus gaps were categorized as having sub-optimal repair. Possessing a Lys/Lys751 genotype increased the risk of sub-optimal DNA repair (odds ratio = 7.2, 95% confidence interval = 1.01-87.7). The Asp312Asn XPD polymorphism did not appear to affect DNA repair proficiency. These results suggest that the Lys751 (common) allele may alter the XPD protein product resulting in sub-optimal repair of X-ray-induced DNA damage.

DNA adduct levels and DNA repair polymorphisms in traffic-exposed workers and a general population sample

“…At the same time, differences in DNA adduct levels between the 2 study groups (exposed workers and volunteers included in the random sample) tended to be restricted to subjects with at least a variant allele. Our results, apparently contrast with a small study by Lunn et al, 15 whereas Sanford et al 35 had not found a higher chromatid aberration frequency in cells containing a rare XPD mutation. Amino acid variants in For each polymorphic gene, subjects with two common alleles were compared with those with one or two polymorphic alleles combined together.-1 p value: Cochran-Mantel-Haenszel test for proportion of positive samples.-2 p value: Wilcoxon rank sum test for DNA adductscomparison between the 2 study groups (random sample subjects and traffic exposed workers) across each genotype.-3 p value: Wilcoxon rank sum test for DNA adducts-comparison between the 2 genotypes within each study group.-4 Some figures do not add up to the total because of some missing values.- 5 From analysis for covariance model including terms for age, sex, smoking history (never, ex and current) and period of blood drawing.-6 Ͼ0.1 DNA adducts/10 9 nucleotides.…”

“…16 Nevertheless, all these results must be confirmed on larger samples and on populations of different origins; actually in our sample from central Italy, the Gln751 allele has a frequency similar to the study carried out by Duell et al 16 in the United States (0.42 vs. 0.39), but higher than 2 other American studies (average frequency 0.27). 14,15 This discrepancy may be because the latter study groups were much smaller (12 and 31 subjects, respectively) in comparison to our and Duell's study (214 and 76 individuals, respectively).…”

“…12 In particular, xeroderma pigmentosum group D (XPD, also known as ERCC2) and x-ray repair cross complementing group 1-3 (XRCC1 and XRCC3) genes have been reported to be polymorphic and might be involved in environmental carcinogenesis. [12][13][14][15][16][17][18] The XRCC1 protein participates in the BER pathway, 19 acting apparently as a scaffold protein, facilitating the repair reaction by binding DNA ligase III at its carboxy and DNA polymerase ␤ to its amino terminus. XRCC3 participates in DNA double-strand break/recombination repair and is a member of an emerging family of Rad-51-related proteins that likely participate in homologous recombination to maintain chromosome stability and repair DNA damage.…”

Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk

“…We also extend our findings to include novel positive associations with two other NER SNPs (ERCC1 8092C/A and ERCC1 118C/T). These findings are in keeping with the known association between NER pathway polymorphisms and alterations in DNA repair capacity [15,16,20,37], and in turn, the increased risk of various cancers associated with diminished repair capacity (e.g., squamous cell carcinoma of the esophagus [12,29,31], lung cancer [18,20,21], breast cancer [17,19], prostate cancer [14], and malignant melanoma [15]). ERCC1 8092C/A has been found to have positive associations in breast cancer risk [38,39], glioma risk [40], and a gene-smoking interaction in lung cancer risk [41].…”

“…Functional variation in DNA repair capacity (DRC) through genetic variation such as single nucleotide polymorphisms (SNPs) of key repair genes is associated with a higher risk of developing various types of cancer [13][14][15][16][17][18][19][20][21][22]. Two DNA repair pathways have been particularly well studied for genetic variation: NER and BER.…”