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DNA repair is indispensable for survival after acute inflammation.

Calvo, JA, Meira, LB, Lee, CY, Moroski-Erkul, CA, Abolhassani, N, Taghizadeh, K, Eichinger, LW, Muthupalani, S, Nordstrand, LM, Klungland, A and Samson, LD (2012) DNA repair is indispensable for survival after acute inflammation. J Clin Invest., 122 (7). pp. 2680-2689.

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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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Microbial and Cellular Sciences
Authors :
AuthorsEmailORCID
Calvo, JAUNSPECIFIEDUNSPECIFIED
Meira, LBUNSPECIFIEDUNSPECIFIED
Lee, CYUNSPECIFIEDUNSPECIFIED
Moroski-Erkul, CAUNSPECIFIEDUNSPECIFIED
Abolhassani, NUNSPECIFIEDUNSPECIFIED
Taghizadeh, KUNSPECIFIEDUNSPECIFIED
Eichinger, LWUNSPECIFIEDUNSPECIFIED
Muthupalani, SUNSPECIFIEDUNSPECIFIED
Nordstrand, LMUNSPECIFIEDUNSPECIFIED
Klungland, AUNSPECIFIEDUNSPECIFIED
Samson, LDUNSPECIFIEDUNSPECIFIED
Date : 2 July 2012
Identification Number : 10.1172/JCI63338
Additional Information : DNA repair is indispensable for survival after acute inflammation. 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 Published in Volume 122, Issue 7 J Clin Invest. 2012; 122(7):2680–2689 doi:10.1172/JCI63338 It appears here by kind permission of the publisher.
Depositing User : Symplectic Elements
Date Deposited : 14 Jan 2014 09:40
Last Modified : 14 Jan 2014 09:40
URI: http://epubs.surrey.ac.uk/id/eprint/714660

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