Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.
Vision loss affects >3 million Americans and many more people worldwide. Although predisposing genes have been identified their link to known environmental factors is unclear. In wild-type animals DNA alkylating agents induce photoreceptor apoptosis and severe retinal degeneration. Alkylation-induced retinal degeneration is totally suppressed in the absence of the DNA repair protein alkyladenine DNA glycosylase (Aag) in both differentiating and postmitotic retinas. Moreover, transgenic expression of Aag activity restores the alkylation sensitivity of photoreceptors in Aag null animals. Aag heterozygotes display an intermediate level of retinal degeneration, demonstrating haploinsufficiency and underscoring that Aag expression confers a dominant retinal degeneration phenotype.alkylation damage ͉ DNA glycosylase ͉ photoreceptors ͉ apoptosis R ods and cones are neuronal photoreceptor cells in the retina responsible for perception of light and color, respectively. Photoreceptor cell death via retinal degeneration leads to blindness and is a hallmark of a group of diseases collectively referred to as retinitis pigmentosa (RP) (1). Mutations in any of at least 45 different genes have been associated with RP, indicating a strong genetic component in retinal degeneration (www. sph.uth.tmc.edu/Retnet/sum-dis.htm). RP-associated retinal degeneration starts by rod cell death followed by cone loss, in a progressive process. Oxidative stress and oxidation-dependent DNA damage are thought to play a role in RP-associated photoreceptor apoptosis, and administration of antioxidants reduces cone cell death in the rd1 mouse, a naturally-occurring mouse model of RP (2). Moreover, in experimental animals, excessive exposure to light (3) or exposure to the radiosensitizer nitroimidazole CI1010 (4, 5) induces retinal degeneration by mechanisms likely involving oxidative stress. Excessive light stimulates shedding of rod outer segments that are phagocytosed by retinal pigment epithelium (RPE) cells in a process that generates an excess of reactive oxygen and nitrogen species (RONS) (6, 7). That excessive light exposure ultimately induces DNA base damage has been inferred from the fact that such exposure induces increased expression of the DNA polymerase  (pol ) base excision repair (BER) enzyme (3). Moreover, a mouse model defective in transcription-coupled repair of oxidative DNA damage, the Csb mutant mouse, was recently reported to manifest retinal degeneration associated with aging or ionizing radiation exposure (8, 9), conditions where increased oxidative stress can occur.Previous studies have shown that treatment with DNA alkylating agents leads to retinal degeneration in rodents (10-12). These studies were performed with the S N 1 alkylating agent methyl nitrosourea (MNU), which reacts with both oxygens and nitrogens in DNA to form 3 major adducts, 7-methylguanine (7MeG; 70-80% of all adducts), O 6 -methylguanine (O 6 MeG; Ϸ10%), and 3-methyladenine (3MeA; Ϸ10%). Increased levels of 7MeG, a lesion believed to be biologically i...
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