title: NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice.
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 AFB1show significant increases in the levels of AFB1-Fapy-dG inNeil1-/-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 inNeil1-/-The magnitude of this effect inNeil1-/-mice is greater than that previously measured inXeroderma pigmentosumcomplementation 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.
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vartanian
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Minko
authors.affiliation: Department of Chemistry, Department Biological Engineering, and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Supawadee
authors.initials: S
authors.lastname: Chawanthayatham
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Egner
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239.|Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Ying-Chih
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Lauriel F
authors.initials: LF
authors.lastname: Earley
authors.affiliation: Knight BioLibrary, Oregon Health & Science University, Portland, OR 97201.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Makar
authors.affiliation: Histopathology Research Core, Oregon Health & Science University, Portland, OR 97201.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Eng
authors.affiliation: Histopathology Research Core, Oregon Health & Science University, Portland, OR 97201.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Camp
authors.affiliation: Department of Chemistry, Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Chemistry, Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lasarev
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205.
authors.forename: John D
authors.initials: JD
authors.lastname: Groopman
authors.affiliation: Department of Chemistry, Department Biological Engineering, and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Croy
authors.affiliation: Department of Chemistry, Department Biological Engineering, and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: John M
authors.initials: JM
authors.lastname: Essigmann
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239.|Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239.|Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: McCullough
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239; lloydst@ohsu.edu.|Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239.|Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239.|Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239.
authors.forename: R Stephen
authors.identifier: 0000-0001-7273-372X
authors.initials: RS
authors.lastname: Lloyd
mesh_terms: D000348:Aflatoxins / Q000633:toxicity*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018736:DNA Adducts / Q000187:drug effects*; D045647:DNA Glycosylases / Q000502:physiology*; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011042:Poisons / Q000633:toxicity; D020011:Protective Agents / Q000494:pharmacology*
chemical_list: D000348:Aflatoxins; D018736:DNA Adducts; D011042:Poisons; D020011:Protective Agents; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse
keywords: aflatoxin; base excision repair; environmental toxicant; liver cancer; ring-fragmented purines