Dataset Information

XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure.

ABSTRACT: Aflatoxin B1 (AFB1), resulting in the formation of AFB1-DNA adducts, is a known human carcinogen. AFB1-exposure individuals with inherited susceptible carcinogen-repairing genotypes may experience an increased risk of genotoxicity. This study was aimed to investigate whether DNA repair gene xerodermapigmentosum complementation group C codon 939 polymorphism (rs2228001) affected the levels of AFB1-DNA adducts in Guangxi Population (n = 2558), from an AFB1-exposure area. AFB1-DNA adducts were measured by ELISA, and XPC codon 939 genotypes were identified by TaqMan-PCR. We found that longer AFB1-exposure years significantly increased XPC genotypes with codon 939 Gln alleles (namely, XPC-LG and -GG, odds ratios [95% confidence intervals] were 1.37 (1.15-1.63) and 1.99 (1.55-2.55), respectively) was significantly associated with higher levels of AFB1-DNA adducts. Furthermore, there was a positive joint effect between XPC genotypes and long-year AFB1 exposure in the formation of AFB1-DNA adducts. These results suggest that individuals with susceptible genotypes XPC-LG and -GG may experience an increased risk of DNA damage elicited by AFB1 exposure.

SUBMITTER: Long XD

PROVIDER: S-EPMC4358568 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure.

Long Xi-Dai XD Huang Hong-Dong HD Huang Xiao-Ying XY Yao Jin-Guang JG Xia Qiang Q

International journal of clinical and experimental medicine 20150115 1

Aflatoxin B1 (AFB1), resulting in the formation of AFB1-DNA adducts, is a known human carcinogen. AFB1-exposure individuals with inherited susceptible carcinogen-repairing genotypes may experience an increased risk of genotoxicity. This study was aimed to investigate whether DNA repair gene xerodermapigmentosum complementation group C codon 939 polymorphism (rs2228001) affected the levels of AFB1-DNA adducts in Guangxi Population (n = 2558), from an AFB1-exposure area. AFB1-DNA adducts were meas ...[more]

PMID: 25785113

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Project description:Aflatoxin B(1) (AFB(1)) is oxidized to an epoxide in vivo, which forms an N7-dG DNA adduct (AFB(1)-N7-dG). The AFB(1)-N7-dG can rearrange to a formamidopyrimidine (AFB(1)-FAPY) derivative. Both AFB(1)-N7-dG and the β-anomer of the AFB(1)-FAPY adduct yield G→T transversions in Escherichia coli, but the latter is more mutagenic. We show that the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) bypasses AFB(1)-N7-dG in an error-free manner but conducts error-prone replication past the AFB(1)-FAPY adduct, including misinsertion of dATP, consistent with the G→T mutations observed in E. coli. Three ternary (Dpo4-DNA-dNTP) structures with AFB(1)-N7-dG adducted template:primers have been solved. These demonstrate insertion of dCTP opposite the AFB(1)-N7-dG adduct, and correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB(1)-N7-dG:dC pair. The insertion of dTTP reveals hydrogen bonding between the template N3 imino proton and the O(2) oxygen of dTTP, and between the template T O(4) oxygen and the N3 imino proton of dTTP, perhaps explaining why this polymerase does not efficiently catalyze phosphodiester bond formation from this mispair. The AFB(1)-N7-dG maintains the 5'-intercalation of the AFB(1) moiety observed in DNA. The bond between N7-dG and C8 of the AFB(1) moiety remains in plane with the alkylated guanine, creating a 16° inclination of the AFB(1) moiety with respect to the guanine. A binary (Dpo4-DNA) structure with an AFB(1)-FAPY adducted template:primer also maintains 5'-intercalation of the AFB(1) moiety. The β-deoxyribose anomer is observed. Rotation about the FAPY C5-N(5) bond orients the bond between N(5) and C8 of the AFB(1) moiety out of plane in the 5'-direction, with respect to the FAPY base. The formamide group extends in the 3'-direction. This improves stacking of the AFB(1) moiety above the 5'-face of the FAPY base, as compared to the AFB(1)-N7-dG adduct. Ternary structures with AFB(1)-β-FAPY adducted template:primers show correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB(1)-β-FAPY:dC pair. For dATP, the oxygen atom of the FAPY formamide group participates in a water-mediated hydrogen bond with Arg332. The insertion of dTTP yields a structure similar to that observed for the AFB(1)-N7-dG adduct. The differential accommodation of these AFB(1) adducts within the active site may, in part, modulate lesion bypass.

Dataset Information

XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure.

Publications

XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure.

Similar Datasets

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