1. NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice.
- Author
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Vartanian V, Minko IG, Chawanthayatham S, Egner PA, Lin YC, Earley LF, Makar R, Eng JR, Camp MT, Li L, Stone MP, Lasarev MR, Groopman JD, Croy RG, Essigmann JM, McCullough AK, and Lloyd RS
- Subjects
- Animals, Carcinoma, Hepatocellular chemically induced, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Female, Liver Neoplasms, Experimental chemically induced, Liver Neoplasms, Experimental metabolism, Liver Neoplasms, Experimental pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Poisons toxicity, Aflatoxins toxicity, Carcinoma, Hepatocellular prevention & control, DNA Adducts drug effects, DNA Glycosylases physiology, Liver Neoplasms, Experimental prevention & control, Protective Agents pharmacology
- Abstract
Global distribution of hepatocellular carcinomas (HCCs) is dominated by its incidence in developing countries, accounting for >700,000 estimated deaths per year, with dietary exposures to aflatoxin (AFB
1 ) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB1 -induced HCCs are poorly understood. Herein, it is shown that the DNA base excision repair (BER) enzyme, DNA glycosylase NEIL1, efficiently recognizes and excises the highly mutagenic imidazole ring-opened AFB1 -deoxyguanosine adduct (AFB1 -Fapy-dG). Consistent with this in vitro result, newborn mice injected with AFB1 show significant increases in the levels of AFB1 -Fapy-dG in Neil1-/- vs. wild-type liver DNA. Further, Neil1-/- mice are highly susceptible to AFB1 -induced HCCs relative to WT controls, with both the frequency and average size of hepatocellular carcinomas being elevated in Neil1-/- The magnitude of this effect in Neil1-/- mice is greater than that previously measured in Xeroderma pigmentosum complementation group A (XPA) mice that are deficient in nucleotide excision repair (NER). Given that several human polymorphic variants of NEIL1 are catalytically inactive for their DNA glycosylase activity, these deficiencies may increase susceptibility to AFB1 -associated HCCs., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
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