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DNA repair is indispensable for survival after acute inflammation
Jennifer A. Calvo, … , Arne Klungland, Leona D. Samson
Jennifer A. Calvo, … , Arne Klungland, Leona D. Samson
Published June 11, 2012
Citation Information: J Clin Invest. 2012;122(7):2680-2689. https://doi.org/10.1172/JCI63338.
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Research Article Oncology Article has an altmetric score of 1

DNA repair is indispensable for survival after acute inflammation

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Abstract

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.

Authors

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

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Figure 5

DSS treatment is lethal to Aag–/–Alkbh2–/–Alkbh3–/– mice.

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DSS treatment is lethal to Aag–/–Alkbh2–/–Alkbh3–/– mice.
 
(A) Kaplan-M...
(A) Kaplan-Meier survival curves of WT (n = 11), Aag–/– (n = 9), and Aag–/–Alkbh2–/–Alkbh3–/– (n = 11) mice following 1 5-day cycle of DSS (2.5%). (B) Examples of colon pathology when the mice became moribund (2 days after DSS withdrawal, 7 days following start of DSS treatment) in Aag–/–Alkbh2–/–Alkbh3–/– mice. WT and Aag–/– mice are shown at completion of study (8 days after DSS withdrawal, 13 days after start of DSS treatment). (C and D) Levels of (C) εA base lesions and (D) 1,N2-εG base lesions are quantitated from colonic epithelium for WT, Aag–/–, and Aag–/–Alkbh2–/–Alkbh3–/– mice under untreated conditions (day 0), immediately following DSS (1.75%) withdrawal (day 5), and 4 days following DSS withdrawal (day 9). Statistical significance was determined by 2-way ANOVA with Bonferroni post test. Data are shown as the mean ± SD. (E) H&E-stained colon sections are shown from all mice 7 days following start of DSS treatment. (F) Histopathological scores of epithelial defects, mucosal degeneration, edema, inflammation, and hyperplasia are shown for WT (n = 10), Aag–/– (n = 10), and Aag–/–Alkbh2–/–Alkbh3–/– (n = 5) mice harvested 7 days following initiation of DSS (2.5%) treatment. Data represent mean ± SEM. (B and E) Asterisk indicate edema; arrows indicate epithelial ulceration. Scale bar: 100 μm.

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