Modulation of nucleotide excision repair in human lymphocytes by genetic and dietary factors

Abstract

Gene-environment interactions determine inter-individual variations in nucleotide excision repair (NER) capacity. Oxidative stress was previously found to inhibit NER, thus supplementation with dietary antioxidants could prevent this inhibition, especially in genetically susceptible subjects. To study the effects of genetic polymorphisms in NER-related genes and dietary intake of antioxidants on an individual's NER capacity, lymphocytes of 168 subjects were isolated before and after a 4-week blueberry and apple juice intervention. Twelve genetic polymorphisms in NER genes XPA, XPC, ERCC1, ERCC2, ERCC5, ERCC6 and RAD23B were assessed by multiplex PCR with single base extension. Based on specific genotype combinations, a subset of individuals (n 36) was selected for phenotypical assessment of NER capacity, which was significantly affected by the total sum of low-activity alleles (P¼ 0·027). The single polymorphism XPA G23A was the strongest predictor of NER capacity (P¼ 0·002); carriers of low-activity alleles AA had about three times lower NER capacity than XPA GG carriers. NER capacity assessed before and after intervention correlated significantly (R 2 0·69; P,0·001), indicating that inter-individual differences in NER capacity are maintained over 4 weeks. Although the intervention increased plasma trolox equivalent antioxidant capacity from 791 (SE 6·61) to 805 (SE 7·90) mM (P¼ 0·032), on average it did not affect NER capacity. Nonetheless, carriers of twelve or more low-activity alleles seemed to benefit from the intervention (P¼ 0·013). Among these, carriers of the variant allele for RAD23B Ala249Val showed improved NER capacity upon intervention (P¼ 0·020). In conclusion, improved NER capacity upon dietary intervention was detected in individuals carrying multiple low-activity alleles. The XPA G23A polymorphism might be a predictor for NER capacity.

Effects of micronutrients on DNA repair

“…While certain studies show similar observations in animals and humans [47], others show contrasting data (effect of folate deficiency; compare [34] and [65]) or effects that are only seen in certain subpopulations with specific compare [49] and [66]). Moreover, while laboratory animals are generally inbred, humans are diverse assortments of several million genetic polymorphisms, which adds to the difficulty of discerning possible effects of micronutrients on DNA repair.…”

“…NER is less often measured than BER. Langie et al [66], supplementing with blueberry and apple juice, reported no effect on NER (with a substrate containing bulky adducts), except that individuals carrying 1 or more low-activity (variant) alleles for XPC-K939Q and/or RAD23B-A249V showed an increase upon the intervention. Brevik et al [62] (measuring NER on a UV-damaged substrate) found a decrease in subjects taking a fruit-and vegetable-rich diet or a kiwifruit supplement.…”

Comet assay to measure DNA repair: approach and applications

“…This unexpected finding gave rise to the speculation that a lower level of DNA damage resulting from primary protection by phytochemicals led to a failure to induce secondary protection in the form of NER enzymes; in other words, repair activity was not needed as the damage level was low. The NER assay was applied by Langie et al (2010b) using a substrate containing benzo(a)pyrene diol epoxide-induced bulky adducts; enhanced repair was seen only in subjects carrying multiple low-activity alleles of repair genes. Recently, Slyskova et al (2014a) analyzed BER and NER capacities in a large cohort of 340 healthy individuals examined for antioxidants intake by food frequency questionnaires and antioxidants plasma levels.…”

Antioxidant Activity and Oxidative Stress: An Overview

“…In addition, other phytochemicals abundant in fruits and vegetable may not only exert unique biological functions, but may also interact synergistically with well recognized antioxidants to promote antioxidant effects. Furthermore, genetic variances, which have been reported to affect the bioavailibility of antioxidants such as vitamin C (Cahill et al 2009 ) and vitamin E (Milman et al 2008 ) and the response to the dietary antioxidant supplementation (Langie et al 2009 ) may affect overall antioxidant capacity in humans. Various biomarkers to determine the antioxidant capacity in a biological system have been developed and advanced.…”

“…Furthermore, a recent study by Cahill et al (2009) indicated that glutathione S -transferease genotypes can infl uence the association between dietary vitamin C and serum ascorbic acid, which in turn could affect the antioxidant capacity. Finally, it has been reported that dietary antioxidant supplementation (blueberry and apple juice mixture) improves the nucleotide excision repair capacity in individuals carrying multiple low -activity alleles, indicating that polymorphisms in a certain gene ( XPA G23A) can predict the value of dietary antioxidants for the nucleotide excision repair capacity (Langie et al 2009 ). Therefore, the bioavailability of antioxidants, the blood response to supplementation with antioxidants, and the oxidative stress associated genomic stability can all be affected by the genetic variance of individuals.…”