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


Hofseth, LJ and Khan, MA and Ambrose, M and Nikolayeva, O and Xu-Welliver, M and Kartalou, M and Hussain, SP and Roth, RB and Zhou, X and Mechanic, LE and Zurer, I and Rotter, V and Samson, LD and Harris, CC, The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation, Journal of Clinical Investigation, 112, (12) pp. 1887-94. ISSN 0021-9738 (2003) [Refereed Article]

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Copyright 2003 American Society for Clinical Investigation

DOI: doi:10.1172/JCI200319757


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.

Item Details

Item Type:Refereed Article
Keywords:ulcerative colitis, DNA repair, base excision repair
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Anthropological genetics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Ambrose, M (Dr Mark Ambrose)
ID Code:87162
Year Published:2003
Web of Science® Times Cited:169
Deposited By:Medicine
Deposited On:2013-11-08
Last Modified:2013-12-10

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