| DNA repair is indispensable for survival after acute inflammation. | |
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MedLine Citation:
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PMID: 22684101 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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More than 15% of cancer deaths worldwide are associated with underlying infections or inflammatory conditions, therefore understanding how inflammation contributes to cancer etiology is important for both cancer prevention and treatment. Inflamed tissues are known to harbor elevated etheno-base (ε-base) DNA lesions induced by the lipid peroxidation that is stimulated by reactive oxygen and nitrogen species (RONS) released from activated neutrophils and macrophages. Inflammation contributes to carcinogenesis in part via RONS-induced cytotoxic and mutagenic DNA lesions, including ε-base lesions. The mouse alkyl adenine DNA glycosylase (AAG, also known as MPG) recognizes such base lesions, thus protecting against inflammation-associated colon cancer. Two other DNA repair enzymes are known to repair ε-base lesions, namely ALKBH2 and ALKBH3; thus, we sought to determine whether these DNA dioxygenase enzymes could protect against chronic inflammation-mediated colon carcinogenesis. Using established chemically induced colitis and colon cancer models in mice, we show here that ALKBH2 and ALKBH3 provide cancer protection similar to that of the DNA glycosylase AAG. Moreover, Alkbh2 and Alkbh3 each display apparent epistasis with Aag. Surprisingly, deficiency in all 3 DNA repair enzymes confers a massively synergistic phenotype, such that animals lacking all 3 DNA repair enzymes cannot survive even a single bout of chemically induced colitis. |
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Authors:
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Jennifer A Calvo; Lisiane B Meira; Chun-Yue I Lee; Catherine A Moroski-Erkul; Nona Abolhassani; Koli Taghizadeh; Lindsey W Eichinger; Sureshkumar Muthupalani; Line M Nordstrand; Arne Klungland; Leona D Samson |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-06-11 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-07-03 Completed Date: 2012-09-11 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 2680-9 Citation Subset: AIM; IM |
Affiliation:
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Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Azoxymethane / pharmacology Carcinogens / pharmacology Colitis / chemically induced, genetics*, metabolism Colon / immunology, pathology Colorectal Neoplasms / chemically induced, genetics, metabolism DNA Glycosylases / genetics*, metabolism DNA Repair* DNA Repair Enzymes / genetics*, metabolism Dextran Sulfate / pharmacology Dioxygenases / genetics*, metabolism Epistasis, Genetic Female Genetic Predisposition to Disease Kaplan-Meier Estimate Lethal Dose 50 Lipopolysaccharides / pharmacology Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Pancreas / immunology, pathology Pancreatitis / chemically induced, genetics*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P30 ES002109/ES/NIEHS NIH HHS; P30-ES02109/ES/NIEHS NIH HHS; R01 CA055042/CA/NCI NIH HHS; R01 CA075576/CA/NCI NIH HHS; R01 CA149261/CA/NCI NIH HHS; R01-CA055042/CA/NCI NIH HHS; R01-CA075576/CA/NCI NIH HHS; R01-CA149261/CA/NCI NIH HHS; T32-ES007020/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carcinogens; 0/Lipopolysaccharides; 25843-45-2/Azoxymethane; 9042-14-2/Dextran Sulfate; EC 1.13.11.-/Dioxygenases; EC 1.14.11.-/ABH3 protein, mouse; EC 1.14.11.-/Alkbh2 protein, mouse; EC 3.2.2.-/3-methyladenine-DNA glycosylase; EC 3.2.2.-/DNA Glycosylases; EC 6.5.1.-/DNA Repair Enzymes |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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