Effect of dna repair gene polymorphisms on BPDE‐DNA adducts in human lymphocytes

Abstract

To determine whether variations in DNA repair genes are related to host DNA damage, we investigated the association between polymorphism in the XPD gene (codon 199, 312, 751) and the XRCC1 gene (codon 194, 399) and the presence of benzo(a)pyrene diolepoxide adducts to lymphocyte DNA (BPDE-DNA) in a group of male patients with incident lung cancer, all current smokers. BPDE-DNA adducts were analyzed by high-resolution gas chromatography-negative ion chemical ionization-mass spectrometry. XPD and XRCC1 genotypes were identified by PCR-RFLP. XRCC1 and XPD genotypes did not affect the levels and proportion of detectable BPDE-DNA adducts. The patients were also genotyped for the GSTM1 polymorphism, given its role in the detoxification of BPDE. Individuals with the GSTM1 deletion had significantly higher levels of BPDE-DNA adducts when they were XPD-Asp312Asp؉Lys751Lys than carriers of at least one variant allele. No such association was found with the XRCC1 genotypes. Because of the small study population (n ‫؍‬ 60), further statistical analysis of possible gene-gene and geneenvironment would not be informative. This is the first study analysing the specific BPDE-DNA adduct in vivo with regard to polymorphic repair genes (XPD, XRCC1) and xenobiotic metabolizing gene (GSTM1). Our results raise the possibility that the XPD-Asp312Asp؉Lys751Lys genotype may increase BPDE-DNA damage; this effect might be evident in individuals who are especially likely to have accumulated damage, probably because of lower detoxification capacity and high environmental exposure.

Association of DNA Base-excision Repair XRCC1, OGG1 and APE1 Gene Polymorphisms with Nasopharyngeal Carcinoma Susceptibility in a Chinese Population

“…Even though devoid of any known enzymatic activity, XRCC1 is thought to act as a scaffold protein, play a coordinating role for consecutive stages of the BER system (Ladiges, 2006), The XRCC1 Arg399Gln polymorphism is located within the XRCC1 BRCA1 carboxyl-terminal domain (BRCT I) and is hypothesized to have functional significance because it is located within a well-conserved region and encodes a nonconservative amino acid change. However, studies examining its relation with markers of DNA damage or DNA repair function have yielded mixed results, with some studies showing a positive relation (Duell et al, 2002;Qu and Morimoto, 2005) and others observing no relation with the variants (Palli et al, 2001;Pastorelli et al, 2002;Tuimala et al, 2002;Hu et al, 2005;Leng et al, 2005;Laantri et al, 2011 ). In present study we found homozygous variants of XRCC1 Arg399Gln had observably associations with NPC risk.…”

XRCC1Polymorphisms and Cancer Risk: A Meta-analysis of 38 Case-Control Studies

“…The presence of the variant Gln 399 allele has been shown to be associated with measurable reduced DNA repair capacity as assessed by the persistence of DNA adducts (4-6), elevated levels of sister chromatid exchanges (5, 7), increased RBC glycophorin A (4), p53 mutations (8), and prolonged cell cycle delay (9). However, Taylor et al (10) reported that whereas BRCT-I is critical for XRCC1-dependent SSBR for maintenance of genetic integrity, the Arg 399 Gln polymorphism in BRCT-I does not have a significant impact on this function and negative findings were also obtained from other individual studies (11)(12)(13). A large number of molecular epidemiologic studies have been conducted to evaluate the role of the Arg 399 Gln polymorphism on cancer risk; however, the results remain conflicting rather than conclusive (6,.…”

XRCC1 Genotype and Breast Cancer: Functional Studies and Epidemiologic Data Show Interactions between XRCC1 Codon 280 His and Smoking

“…Some laboratory investigations of XRCC1 codon 399 Gln functionality in human cells suggested that this polymorphism is associated with increased levels of DNA damage after exposure to various mutagens (17)(18)(19). Other reports offered conflicting evidence, suggesting that the 399Gln polymorphism has no adverse effect on DNA repair (20)(21)(22). The 194Trp variant protein does not seem to negatively alter the DNA repair capacity of human cells (18,20).…”