DNA repair is indispensable for survival after acute inflammation

• Published in: The Journal of clinical investigation 2012-07, Vol.122 (7), p.2680-2689
• Main Authors: Calvo, Jennifer A, Meira, Lisiane B, Lee, Chun-Yue I, Moroski-Erkul, Catherine A, Abolhassani, Nona, Taghizadeh, Koli, Eichinger, Lindsey W, Muthupalani, Sureshkumar, Nordstrand, Line M, Klungland, Arne, Samson, Leona D
• Format: Article
• Language: English
• Subjects: AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Animals; Azoxymethane - pharmacology; Biomedical research; Cancer; Carcinogens - pharmacology; Colitis - chemically induced; Colitis - genetics; Colitis - metabolism; Colon - immunology; Colon - pathology; Colorectal cancer; Colorectal Neoplasms - chemically induced; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Complications and side effects; Dextran Sulfate - pharmacology; Dioxygenases - genetics; Dioxygenases - metabolism; Disease prevention; DNA damage; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA Repair; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Enzymes; Epistasis, Genetic; Female; Genetic Predisposition to Disease; Inflammation; Inflammatory bowel disease; Kaplan-Meier Estimate; Lethal Dose 50; Lipid peroxidation; Lipopolysaccharides - pharmacology; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Pancreas - immunology; Pancreas - pathology; Pancreatitis - chemically induced; Pancreatitis - genetics; Pancreatitis - metabolism
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI63338

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.