NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice
Name
NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice
Size
1.42 MB
Format
Unknown
Checksum (MD5)
c2591c0bd3b71c4039238a82eac82f90
Author(s)
Vartanian, Vladimir
Minko, Irina G.
Egner, Patricia A.
Lin, Ying-Chih
Earley, Lauriel F.
Makar, Rosemary
Eng, Jennifer R.
Camp, Matthew T.
Li, Liang
Stone, Michael P.
Date Issued
April 2017
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Vartanian, Vladimir et al. “NEIL1 Protects Against Aflatoxin-Induced Hepatocellular Carcinoma in Mice.” Proceedings of the National Academy of Sciences 114, 16 (April 2017): 4207–4212 © 2017 National Academy of Sciences
Version
Final published version
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]) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB[subscript 1]-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 1 -deoxyguanosine adduct (AFB[subscript 1]-Fapy-dG). Consistent with this in vitro result, newborn mice injected with AFB[subscript 1] show significant increases in the levels of AFB[subscript 1]-Fapy-dG in Neil1[superscript -/-] vs. wild-type liver DNA. Further, Neil1[superscript -/-] mice are highly susceptible to AFB[subscript 1]-induced HCCs relative to WT controls, with both the frequency and average size of hepatocellular carcinomas being elevated in Neil1[superscript -/-]. The magnitude of this effect in Neil1[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]-associated HCCs.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/PNAS.1620932114
