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Application of Laser Micro-irradiation for Examination of Single and Double Strand Break Repair in Mammalian Cells
Published on: September 5, 2017
Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2
Yawei Qiao1, Margaret R Spitz, Hongbing Shen
1Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, 1515 Holcombe Boulevard, TX 77030, USA.
Abstract:
DNA repair capacity (DRC) plays an important role in genetic susceptibility to cancer. Polymorphisms of a number of DNA repair genes involved in several distinct pathways have been identified. However, their effects on repair function have not been well characterized. We demonstrated previously that DRC for removal of benzo[a]pyrene diol epoxide-induced DNA damage measured by a host-cell reactivation assay was modulated by two XPD/ERCC2 polymorphisms in lung cancer. In this report, we investigated the association between the repair phenotype of ultraviolet (UV)-induced damage and genotypes of three DNA repair genes, XPC and XPD [involved in nucleotide excision repair (NER)] and XRCC1 [involved in base excision repair (BER)]. We measured DRC for removal of UV photoproducts by the host-cell reactivation assay in cryopreserved lymphocytes from 102 healthy non-Hispanic white subjects. We also typed these subjects for five polymorphisms in these three DNA repair genes (at intron 9 of XPC; exons 6, 10 and 23 of XPD and exon 10 of XRCC1). Compared with wild-type homozygotes, subjects homozygous for polymorphisms of the two NER genes consistently had suboptimal DRC. The DRC was consistently lower in subjects homozygous for XPC, XPD or both than in subjects with other genotypes, although the difference was not statistically significant for XPD variants. In contrast, the polymorphic allele of the BER gene, XRCC1, had no consistent effect on DRC. We concluded that these NER polymorphisms may modulate DRC and may be useful biomarkers for identifying individuals at risk of developing cancer.
Insights
Genetic variations in DNA repair genes impact cancer risk. Specific polymorphisms in nucleotide excision repair genes (XPC, XPD) were linked to reduced DNA repair capacity, suggesting potential cancer risk biomarkers.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- DNA repair capacity (DRC) is crucial for preventing genetic mutations that lead to cancer.
- Genetic variations (polymorphisms) in DNA repair genes can influence an individual's susceptibility to cancer.
- Previous studies showed XPD/ERCC2 polymorphisms affect DNA damage repair from benzo[a]pyrene diol epoxide.
Purpose of the Study:
- To investigate the association between DNA repair gene polymorphisms and the repair phenotype of ultraviolet (UV)-induced DNA damage.
- To evaluate the impact of XPC, XPD (nucleotide excision repair - NER), and XRCC1 (base excision repair - BER) gene polymorphisms on DNA repair capacity.
Main Methods:
- Host-cell reactivation assay was used to measure DRC for UV-induced DNA damage in lymphocytes from 102 healthy individuals.
- Genotyping was performed for five polymorphisms in XPC, XPD, and XRCC1 genes.
- Subjects were classified based on their genotypes, comparing wild-type homozygotes with carriers of specific polymorphisms.
Main Results:
- Homozygosity for polymorphisms in XPC and XPD (NER genes) was associated with consistently suboptimal DNA repair capacity.
- Individuals homozygous for XPC, XPD, or both exhibited lower DRC compared to other genotypes, though XPD effects were not statistically significant.
- Polymorphisms in the XRCC1 gene (BER gene) did not show a consistent effect on DNA repair capacity.
Conclusions:
- Nucleotide excision repair gene polymorphisms (XPC, XPD) may modulate DNA repair capacity.
- These NER polymorphisms could serve as potential biomarkers for identifying individuals at increased cancer risk.
- Base excision repair gene polymorphisms (XRCC1) did not appear to significantly impact UV-induced DNA damage repair in this study.
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