Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 751, Issue -, Pages 49-54Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2013.08.005
Keywords
DNA repair; Nucleotide excision repair; Comet assay; Genotype-phenotype association; ERCC4; MBD4
Funding
- Associazione Italiana per la Ricerca sul Cancro (Italy)
- Progetto Integrato Oncologia, Regione Toscana-Ministero della Salute Identification of population risk profiles as an approach to cancer prevention
- Environmental Cancer Risk Nutrition and Individual Susceptibility project
- European Commission [266198]
- Compagnia di San Paolo (Turin, Italy)
- Progetto Ricerca Sanitaria Finalizzata Regione Piemonte
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Inter-individual differences in DNA repair capacity (DRC) may lead to genome instability and, consequently, modulate individual cancer risk. Among the different DNA repair pathways, nucleotide excision repair (NER) is one of the most versatile, as it can eliminate a wide range of helix-distorting DNA lesions caused by ultraviolet light irradiation and chemical mutagens. We performed a genotype-phenotype correlation study in 122 healthy subjects in order to assess if any associations exist between phenotypic profiles of NER and DNA repair gene single nucleotide polymorphisms (SNPs). Individuals were geno-typed for 768 SNPs with a custom Illumina Golden Gate Assay, and peripheral blood mononuclear cells (PBMCs) of the same subjects were tested for a NER comet assay to measure DRC after challenging cells by benzo(a)pyrene diolepoxide (BPDE). We observed a large inter-individual variability of NER capacity, with women showing a statistically significant lower DRC (mean +/- SD: 6.68 +/- 4.76; p = 0.004) than men (mean +/- SD: 8.89 +/- 5.20). Moreover, DRC was significantly lower in individuals carrying a variant allele for the ERCC4 rs1800124 non-synonymous SNP (nsSNP) (p = 0.006) and significantly higher in subjects with the variant allele of MBD4 rs2005618 SNP (p = 0.008), in linkage disequilibrium (r(2) = 0.908) with rs10342 nsSNP. Traditional in silico docking approaches on protein-DNA and protein-protein interaction showed that Gly875 variant in ERCC4 (rs1800124) decreases the DNA-protein interaction and that Ser273 and Thr273 variants in MBD4 (rs10342) indicate complete loss of protein-DNA interactions. Our results showed that NER inter-individual capacity can be modulated by cross-talk activity involving nsSNPs in ERCC4 and MBD4 genes, and they suggested to better investigate SNP effect on cancer risk and response to chemo- and radiotherapies. (C) 2013 Elsevier B.V. All rights reserved.
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