title: 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.
authors.affiliation: Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, National Institutes of Health, MD C3-03, PO Box 12233, Research Triangle Park, NC 27709, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Lunn
authors.forename: K J
authors.initials: KJ
authors.lastname: Helzlsouer
authors.forename: R
authors.initials: R
authors.lastname: Parshad
authors.forename: D M
authors.initials: DM
authors.lastname: Umbach
authors.forename: E L
authors.initials: EL
authors.lastname: Harris
authors.forename: K K
authors.initials: KK
authors.lastname: Sanford
authors.forename: D A
authors.initials: DA
authors.lastname: Bell
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D002869:Chromosome Aberrations; D004247:DNA / Q000528:radiation effects; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D011836:Radiation Tolerance; D014157:Transcription Factors; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004247:DNA; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human