NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice

Vladimir Vartanian, Irina G. Minko, Supawadee Chawanthayatham, Patricia A. Egner, Ying Chih Lin, Lauriel F. Earley, Rosemary Makar, Jennifer R. Eng, Matthew T. Camp, Liang Li, Michael P. Stone, Michael R. Lasarev, John D. Groopman, Robert G. Croy, John M. Essigmann, Amanda K. McCullough, R. Stephen Lloyd

Research output: Research - peer-reviewArticle

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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 (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.

LanguageEnglish (US)
Pages4207-4212
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number16
DOIs
StatePublished - Apr 18 2017

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Aflatoxins
Hepatocellular Carcinoma
DNA Glycosylases
DNA Repair
DNA
N6-(2-deoxy-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine
Xeroderma Pigmentosum
Deoxyguanosine
DNA Adducts
Developing Countries
Liver
Incidence
Enzymes
In Vitro Techniques
imidazole

Keywords

  • Aflatoxin
  • Base excision repair
  • Environmental toxicant
  • Liver cancer
  • Ring-fragmented purines

ASJC Scopus subject areas

  • General

Cite this

NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice. / Vartanian, Vladimir; Minko, Irina G.; Chawanthayatham, Supawadee; Egner, Patricia A.; Lin, Ying Chih; Earley, Lauriel F.; Makar, Rosemary; Eng, Jennifer R.; Camp, Matthew T.; Li, Liang; Stone, Michael P.; Lasarev, Michael R.; Groopman, John D.; Croy, Robert G.; Essigmann, John M.; McCullough, Amanda K.; Lloyd, R. Stephen.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 16, 18.04.2017, p. 4207-4212.

Research output: Research - peer-reviewArticle

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 & Lloyd, RS 2017, 'NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice' Proceedings of the National Academy of Sciences of the United States of America, vol 114, no. 16, pp. 4207-4212. DOI: 10.1073/pnas.1620932114
Vartanian, Vladimir ; Minko, Irina G. ; Chawanthayatham, Supawadee ; Egner, Patricia A. ; Lin, Ying Chih ; Earley, Lauriel F. ; Makar, Rosemary ; Eng, Jennifer R. ; Camp, Matthew T. ; Li, Liang ; Stone, Michael P. ; Lasarev, Michael R. ; Groopman, John D. ; Croy, Robert G. ; Essigmann, John M. ; McCullough, Amanda K. ; Lloyd, R. Stephen. / NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 16. pp. 4207-4212
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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 (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.",
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AU - Minko,Irina G.

AU - Chawanthayatham,Supawadee

AU - Egner,Patricia A.

AU - Lin,Ying Chih

AU - Earley,Lauriel F.

AU - Makar,Rosemary

AU - Eng,Jennifer R.

AU - Camp,Matthew T.

AU - Li,Liang

AU - Stone,Michael P.

AU - Lasarev,Michael R.

AU - Groopman,John D.

AU - Croy,Robert G.

AU - Essigmann,John M.

AU - McCullough,Amanda K.

AU - Lloyd,R. Stephen

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