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NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Apr 18; Vol. 114 (16), pp. 4207-4212. Date of Electronic Publication: 2017 Apr 03. - Publication Year :
- 2017
-
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 <subscript>1</subscript> ) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB <subscript>1</subscript> -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 AFB <subscript>1</subscript> -deoxyguanosine adduct (AFB <subscript>1</subscript> -Fapy-dG). Consistent with this in vitro result, newborn mice injected with AFB <subscript>1</subscript> show significant increases in the levels of AFB <subscript>1</subscript> -Fapy-dG in Neil1 <superscript> -/- </superscript> vs. wild-type liver DNA. Further, Neil1 <superscript> -/- </superscript> mice are highly susceptible to AFB <subscript>1</subscript> -induced HCCs relative to WT controls, with both the frequency and average size of hepatocellular carcinomas being elevated in Neil1 <superscript> -/- </superscript> The magnitude of this effect in Neil1 <superscript> -/- </superscript> 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 AFB <subscript>1</subscript> -associated HCCs.<br />Competing Interests: The authors declare no conflict of interest.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 28373545
- Full Text :
- https://doi.org/10.1073/pnas.1620932114