NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice

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 (AFB₁) 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.