Functional Characterization of Polymorphisms in DNA Repair Genes Using Cytogenetic Challenge Assays

Environ Health Perspect. 2003 Nov;111(15):1843-50. doi: 10.1289/ehp.6632.


A major barrier to understanding the role of polymorphic DNA repair genes for environmental cancer is that the functions of variant genotypes are largely unknown. Using our cytogenetic challenge assays, we conducted an investigation to address the deficiency. Using X-rays or ultraviolet (UV) light, we irradiated blood lymphocytes from 80 nonsmoking donors to challenge the cells to repair the induced DNA damage, and we analyzed expression of chromosome aberrations (CA) specific to the inducing agents. We have genotyped polymorphic DNA repair genes preferentially involved with base excision repair (BER) and nucleotide excision repair (NER) activities (XRCC1, XRCC3, APE1, XPD) corresponding to the repair of X-ray- and UV light-induced DNA damage, respectively. We expected that defects in specific DNA repair pathways due to polymorphisms would cause corresponding increases of specific CA. From our data, XRCC1 399Gln and XRCC3 241Met were associated with significant increases in chromosome deletions compared with the corresponding homozygous wild types (18.27 1.1 vs 14.79 1.2 and 18.22 0.99 vs 14.20 1.39, respectively); XPD 312Asn and XPD 751Gln were associated with significant increases in chromatid breaks compared with wild types (16.09 1.36 vs 11.41 0.98 and 16.87 1.27 vs 10.54 0.87, respectively), p < 0.05. The data indicate that XRCC1 399Gln and XRCC3 241Met are significantly defective in BER, and the XPD 312Asn and XPD 751Gln are significantly defective in NER. In addition, the variant genotypes interact significantly, with limited overlap of the two different repair pathways.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Chromosome Aberrations
  • DNA Damage*
  • DNA Helicases*
  • DNA Repair / genetics*
  • DNA-Binding Proteins / genetics*
  • Environmental Exposure
  • Female
  • Genotype
  • Humans
  • Lymphocytes
  • Male
  • Neoplasms / genetics
  • Neoplasms / physiopathology
  • Polymorphism, Genetic*
  • Proteins / genetics
  • Transcription Factors*
  • Ultraviolet Rays / adverse effects
  • X-ray Repair Cross Complementing Protein 1
  • Xenobiotics / poisoning
  • Xeroderma Pigmentosum Group D Protein


  • DNA-Binding Proteins
  • Proteins
  • Transcription Factors
  • X-ray Repair Cross Complementing Protein 1
  • X-ray repair cross complementing protein 3
  • XRCC1 protein, human
  • Xenobiotics
  • DNA Helicases
  • Xeroderma Pigmentosum Group D Protein
  • ERCC2 protein, human