The adaptive imbalance in base excision–repair enzymes generates microsatellite instability in chronic inflammation

Abstract

Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology.

p53 functions in the incorporation step in DNA base excision repair in mouse liver mitochondria

“…In support of this notion, Habano et al (2000) found a direct association between alterations in the p53 gene and microsatellite instability in both the nuclear and the mitochondrial genomes. We (Hofseth et al, 2003) and others (Yamada and Farber, 2002) have shown that an adaptive imbalance in BER enzymes can cause microsatellite instability, including during ulcerative colitis, a chronic inflammatory disease. In addition, nitric oxide, which is produced in mitochondria at high levels, can increase 3-methyl Adenine glycosylase activity and cause deamination of cytosine …”

Alloreactive microenvironment after human hematopoietic cell transplantation induces genomic alterations in epithelium through an ROS-mediated mechanism: in vivo and in vitro study and implications to secondary neoplasia

“…6,42,43 Furthermore, intracellular-produced free radicals cause direct oxidative DNA damage that may overwhelm the capacity of repair pathways. 42,44 Finally, ROS may induce DNA alterations indirectly by oxidation and inactivation of repair proteins. 6,45 MSI has been mainly associated with cancer 14 or cancer risk.…”

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

“…It has been demonstrated that in ulcerative colitis, a chronic inflammatory condition associated with a predisposition to colon cancer, ⑀C levels were higher than in normal colon, whereas ⑀A was lower (62); also, in colon cancer biopsies, the level of ⑀C was 30 times higher than that of ⑀A (63). Recently, it has been shown that inflammation in ulcerative colitis is correlated with an increased level of ANPG, which in turn produces instability at microsatellite sequences in various types of cells in the affected tissue (64). Based on these observations, we propose that abortive repair of LPO-induced ⑀C may have profound biological implications.…”