Functional analyses of single nucleotide polymorphic variants of the DNA glycosylase NEIL1 in sub-Saharan African populations

Zuckerman, Jamie T.; Minko, Irina G.; Kant, Melis; Jaruga, Pawel; Stone, Michael P.; Dizdaroglu, Miral; McCullough, Amanda K.; Lloyd, R. Stephen

doi:10.1016/j.dnarep.2023.103544

Cited by 3 publications

(1 citation statement)

References 70 publications

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“…Given the importance of NEIL1 in the maintenance of genomic integrity following aflatoxin exposures in a mouse model ( 31 ) and the possibility that pathogenic polymorphic variants of NEIL1 ( 37 , 40–42 ) may affect human HCC risk, the current study was designed to investigate whether the mutagenic frequencies and spectra, including distribution of mutations across trinucleotide sequences, are altered in NEIL1-deficient versus proficient mice. To address this question, we employed ultra-high accuracy Duplex Sequencing (DuplexSeq) ( 43–45 ).…”

Section: Introductionmentioning

confidence: 99%

Frequencies and spectra of aflatoxin B1-induced mutations in liver genomes of NEIL1-deficient mice as revealed by duplex sequencing

Minko,

Luzadder,

Vartanian

et al. 2024

NAR Molecular Medicine

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Increased risk for the development of hepatocellular carcinoma (HCC) is driven by a number of etiological factors including hepatitis viral infection and dietary exposures to foods contaminated with aflatoxin-producing molds. Intracellular metabolic activation of aflatoxin B1 (AFB1) to a reactive epoxide generates highly mutagenic AFB1-Fapy-dG adducts. Previously, we demonstrated that repair of AFB1-Fapy-dG adducts can be initiated by the DNA glycosylase NEIL1 and that male Neil1−/− mice were significantly more susceptible to AFB1-induced HCC relative to wild-type mice. To investigate the mechanisms underlying this enhanced carcinogenesis, WT and Neil1−/− mice were challenged with a single, 4 mg/kg dose of AFB1 and frequencies and spectra of mutations were analyzed in liver DNAs 2.5 months post-injection using duplex sequencing. The analyses of DNAs from AFB1-challenged mice revealed highly elevated mutation frequencies in the nuclear genomes of both males and females, but not the mitochondrial genomes. In both WT and Neil1−/− mice, mutation spectra were highly similar to the AFB1-specific COSMIC signature SBS24. Relative to wild-type, the NEIL1 deficiency increased AFB1-induced mutagenesis with concomitant elevated HCCs in male Neil1−/− mice. Our data establish a critical role of NEIL1 in limiting AFB1-induced mutagenesis and ultimately carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Frequencies and spectra of aflatoxin B1-induced mutations in liver genomes of NEIL1-deficient mice as revealed by duplex sequencing

Minko,

Luzadder,

Vartanian

et al. 2024

NAR Molecular Medicine

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Functional characterization of single nucleotide polymorphic variants of DNA repair enzyme NEIL1 in South Asian populations

Zuckerman,

Jackson,

Minko

et al. 2024

DNA Repair

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When less is more: The association between the expression of polymorphic CYPs and AFB1‐induced HCC

Mohamed,

Armanious,

Bedair

et al. 2024

Eur J Clin Investigation

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BackgroundAn individual’s genetic fingerprint is emerging as a pivotal predictor of numerous disease‐ and treatment‐related factors. Single nucleotide polymorphisms (SNPs) in drug‐metabolizing enzymes play key roles in an individual’s exposure to a malignancy‐associated risk, such as Aflatoxin B1 (AFB1)‐induced hepatocellular carcinoma (HCC).AimThis study aimed at reviewing literature on the polymorphisms that exist in CYP enzymes and their possible link with susceptibility to AFB1‐induced HCC.Materials & MethodsA set of keywords associated with the study subject of interest was used to search the Google Scholar and the PubMed database. The last ten years’ worth of research projects were included in the results filter. The research involved HCC patients and any connection between polymorphic forms of CYP enzymes and their susceptibility to AFB1‐induced HCC, including older but significant data.ResultsVariations in CYP1A2 and CYP3A4 were reported to impact the rate and magnitude of AFB1 bio‐activation, thus influencing an individual’s vulnerability to develop HCC. In HCC patients, the activity of CYP isoforms varies, where increased activity has been reported with CYP2C9, CYP2D6, and CYP2E1, while CYP1A2, CYP2C8, and CYP2C19 exhibit decreased activity. CYP2D6*10 frequency has been discovered to differ considerably in HCC patients. Rs2740574 (an upstream polymorphism in CYP3A4 as detected in CYP3A4*1B) and rs776746 (which affects CYP3A5 RNA splicing), both of which influence CYP3A expression, thus impacting the variability of AFB1‐epoxide adducts in HCC patients.DiscussionCYP1A2 is the primary enzyme accountable for the formation of harmful AFBO globally. CYP3A4, CYP3A5, CYP3A7, CYP2B7, and CYP3A3 are also implicated in the bio‐activation of AFB1 to mutagenic metabolites. It is thought that CYP3A4 is the protein that interacts with AFB1 metabolism the most.ConclusionPolymorphic variants of CYP enzymes have a functional impact on the susceptibility to AFB1‐induced HCC. Outlining such variation and their implications may provide deeper insights into approaching HCC in a more personalized manner for guiding future risk‐assessment, diagnosis, and treatment.

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Functional analyses of single nucleotide polymorphic variants of the DNA glycosylase NEIL1 in sub-Saharan African populations

Cited by 3 publications

References 70 publications

Frequencies and spectra of aflatoxin B1-induced mutations in liver genomes of NEIL1-deficient mice as revealed by duplex sequencing

Frequencies and spectra of aflatoxin B1-induced mutations in liver genomes of NEIL1-deficient mice as revealed by duplex sequencing

Functional characterization of single nucleotide polymorphic variants of DNA repair enzyme NEIL1 in South Asian populations

When less is more: The association between the expression of polymorphic CYPs and AFB1‐induced HCC

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