Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: role in mutagen sensitivity

Abstract

Mutagen sensitivity, measuring the extent of chromosome damage induced by an in vitro treatment of peripheral lymphocytes with bleomycin, has been associated with an increased risk of various human cancers. Sensitivity to bleomycin appears to have high heritability and is usually considered to reflect individual capacity to repair DNA lesions. Another potential contributor to variation in bleomycin sensitivity could be inherited differences in the metabolism of bleomycin. We assessed whether genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes (XMEs) could explain bleomycin sensitivity. Frequencies of bleomycin-induced chromatid breaks per cell (b/c) were determined for 80 healthy Caucasians. Genotypes of DNA repair genes XRCC (X-ray repair cross-complementing) 1 and 3 and XME genes bleomycin hydrolase (BLHX), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) were analyzed from leukocyte DNA using methods based on polymerase chain reaction. The mean number of chromatid b/c was increased in individuals with XRCC1 codon 280 variant allele (P = 0.002; two-sided Mann-Whitney test). Smokers carrying BLHX codon 1450 variant allele showed a decrease in the mean number of chromatid b/c (P = 0.036). In multiple linear regression models including adjustment for age, sex, smoking and genotype, the adjusted relative risks (and 95% confidence intervals) were 1.18 (0.98-1.41) and 0.84 (0.69-1.00) for carriers of XRCC1 codon 280 and BLHX codon 1450 variant alleles, respectively. XRCC1 codon 280 polymorphism had a significant effect (P = 0.012) in predetermining whether the individual was classified as non-sensitive, sensitive or hypersensitive to bleomycin. Although based on relatively few individuals, our results suggest that bleomycin sensitivity is partially explained by genetic polymorphisms affecting DNA repair (XRCC1) and in vitro metabolism of bleomycin (BLHX).

Predictive Value of XRCC1 and XRCC3 Gene Polymorphisms for Risk of Ovarian Cancer Death After Chemotherapy

“…The mutations of XRCC1 polymorphisms may increase the risk of cancers by impairing the interaction of XRCC1 with other enzymatic proteins and consequently altering DNA repair activity (Basso et al, 2007;Tudek, 2007), and resulted in carcinogenesis development. Our study found significant an odds ratio of codon 399 Gln allele for ovarian cancer, which strongly implicates that these polymorphisms may alter the normal protein function by encoding for a twisted protein (Tuimala et al, 2002), resulting in altered affinity to its interactive proteins suggesting an association with a deficiency in DNA repair capacity. This finding indicated the XRCC1 gene variants in the impairment of DNA repair mechanism and their consequent biological effect could induce the carcinogenesis.…”

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.…”

Role of DNA mismatch repair genetic polymorphisms in the risk of childhood acute lymphoblastic leukaemia

“…These results support the notion that the aetiology of childhood ALL is more likely to depend upon interactions of many genes from different metabolic pathways, such as carcinogen metabolism and DNA repair. This is supported by a recent report indicating that mutagen sensitivity in lymphocytes of certain individuals could be associated with DNA variants in DNA repair and xenobioticmetabolizing enzymes (Tuimala et al, 2002). Other mechanisms involving MMR proteins cannot be completely ruled out, because these proteins participate in different vital cellular processes, including homologous recombination (de Wind et al, 1995), G2 checkpoint control (Hawn et al, 1995), recognition of DNA damage and/or apoptosis (Kat et al, 1993), as well as in transcription-coupled repair (Mellon et al, 1996).…”