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 (AFB[subscript 1]) and subsequent DNA adduct formation being a significant driver. Genetic variants tha...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
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National Academy of Sciences (U.S.)
2018
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| Online Access: | http://hdl.handle.net/1721.1/113226 https://orcid.org/0000-0003-0176-1920 https://orcid.org/0000-0002-2196-5691 |
| _version_ | 1811071167037964288 |
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| author | 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. Lasarev, Michael R. Groopman, John D. McCullough, Amanda K. Lloyd, R. Stephen Chawanthayatham, Supawadee Croy, Robert G Essigmann, John M |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences 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. Lasarev, Michael R. Groopman, John D. McCullough, Amanda K. Lloyd, R. Stephen Chawanthayatham, Supawadee Croy, Robert G Essigmann, John M |
| author_sort | Vartanian, Vladimir |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:47:04Z |
| format | Article |
| id | mit-1721.1/113226 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:47:04Z |
| publishDate | 2018 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1132262019-05-17T07:57:19Z NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice 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. Lasarev, Michael R. Groopman, John D. McCullough, Amanda K. Lloyd, R. Stephen Chawanthayatham, Supawadee Croy, Robert G Essigmann, John M Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Chawanthayatham, Supawadee Croy, Robert G Essigmann, John M 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. National Institutes of Health (U.S.) (Grant R01-ES016313) National Institutes of Health (U.S.) (Grant P30-ES002109) National Institutes of Health (U.S.) (Grant R01-CA080024) 2018-01-19T14:30:39Z 2018-01-19T14:30:39Z 2017-04 2016-12 2018-01-17T11:57:28Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/113226 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 PUBLISHER_POLICY https://orcid.org/0000-0003-0176-1920 https://orcid.org/0000-0002-2196-5691 http://dx.doi.org/10.1073/PNAS.1620932114 Proceedings of the National Academy of Sciences 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. application/octet-stream National Academy of Sciences (U.S.) |
| spellingShingle | 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. Lasarev, Michael R. Groopman, John D. McCullough, Amanda K. Lloyd, R. Stephen Chawanthayatham, Supawadee Croy, Robert G Essigmann, John M NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice |
| title | NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice |
| title_full | NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice |
| title_fullStr | NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice |
| title_full_unstemmed | NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice |
| title_short | NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice |
| title_sort | neil1 protects against aflatoxin induced hepatocellular carcinoma in mice |
| url | http://hdl.handle.net/1721.1/113226 https://orcid.org/0000-0003-0176-1920 https://orcid.org/0000-0002-2196-5691 |
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