The Mutyh Base Excision Repair Gene Influences the Inflammatory Response in a Mouse Model of Ulcerative Colitis

Abstract

BackgroundThe Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh−/− mice to oxidative stress.Methodology/Principal FindingsThe severity of colitis, changes in expression of genes involved in DNA repair and inflammation, DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium (DSS). The Mutyh−/− phenotpe was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice. A single DSS cycle induced severe acute ulcerative colitis in wild-type mice, whereas lesions were modest in Mutyh−/− mice, and this was associated with moderate variations in the expression of several cytokines. Eight DSS cycles caused chronic colitis in both wild-type and Mutyh−/− mice. Lymphoid hyperplasia and a significant reduction in Foxp3+ regulatory T cells were observed only in Mutyh−/− mice.ConclusionsThe findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response.

Apurinic/apyrimidinic endonuclease 1, the sensitive marker for DNA deterioration in dextran sulfate sodium-induced acute colitis

“…8,[12][13][14][15][16][17][18] We were interested in the relationship between MMR and BER in preventing DNA damage against DSS-induced colitis in young rats because MYH, which is involved in BER, is also associated with the development of colorectal cancer, and its activity is modulated by MMR and APE1. 20,21 We found that APE1 and MSH2 levels increased significantly at DSS-3d and DSS-5d, respectively. The difference in MSH2 and APE1 expression was significant.…”

“…Therefore, an alternative DNA repair pathway is likely involved in the process of dysplastic change; we hypothesized that BER was the best candidate. While reports of the association of BER with the [19][20][21] we hypothesized that APE1 is another important candidate. APE1 is a dual-function protein that serves as an endonuclease for abasic sites in BER and modulates or activates several transcription factors, including p53, NF-κB, Egr-1, c-Myb, HLF, and Pax-8.…”

“…Additionally, base excision repair (BER) factors, including Ogg1, MutY DNA glycosylase, and MutY homolog (MYH), recognize and excise oxidative DNA damage in the colon. [19][20][21] BER activities are associated with increased oxidative DNA damage, including 8-oxoguanine and 8-hydroxy-deoxyguanosine (8-OHdG). 19,21 Specifically, mutations in the MYH gene are responsible for colorectal cancer, and the activity of the encoded protein is modulated by several factors, including proliferating cell nuclear antigen (PCNA), MMR enzymes (MSH2/MSH6), and apurinic/apyrimidinic endonuclease 1 (APE1).…”

“…[19][20][21] BER activities are associated with increased oxidative DNA damage, including 8-oxoguanine and 8-hydroxy-deoxyguanosine (8-OHdG). 19,21 Specifically, mutations in the MYH gene are responsible for colorectal cancer, and the activity of the encoded protein is modulated by several factors, including proliferating cell nuclear antigen (PCNA), MMR enzymes (MSH2/MSH6), and apurinic/apyrimidinic endonuclease 1 (APE1). 20,21 Colitis can be induced in young rodents by lower DSS concentrations (1-2% w/v) compared to adults (5% w/v) because young animals show increased sensitivity to DSS.…”

“…19,21 Specifically, mutations in the MYH gene are responsible for colorectal cancer, and the activity of the encoded protein is modulated by several factors, including proliferating cell nuclear antigen (PCNA), MMR enzymes (MSH2/MSH6), and apurinic/apyrimidinic endonuclease 1 (APE1). 20,21 Colitis can be induced in young rodents by lower DSS concentrations (1-2% w/v) compared to adults (5% w/v) because young animals show increased sensitivity to DSS. 22 The syndrome evoked in young rats by a lower DSS concentration is similar to that in adult animals, although in young animals, symptoms appear earlier and toxicity is greater than in adults.…”