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Nucleic Acids Research 2005 33(9):2859-2867; doi:10.1093/nar/gki601
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Published online 19 May 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

N-methylpurine DNA glycosylase overexpression increases alkylation sensitivity by rapidly removing non-toxic 7-methylguanine adducts

M. L. Rinne1, Y. He2, B. F. Pachkowski4, J. Nakamura4 and M. R. Kelley1,2,3,*

1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine Indianapolis, IN 46202, USA 2Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine Indianapolis, IN 46202, USA 3Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, IN 46202, USA 4Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina Chapel Hill, NC 27599, USA

*To whom correspondence should be addressed. Tel: +1 317 274 2755; Fax: +1 317 278 9298; Email: mkelley{at}iupui.edu

Received March 17, 2005. Revised April 29, 2005. Accepted April 29, 2005.

Previous studies indicate that overexpression of N-methylpurine DNA glycosylase (MPG) dramatically sensitizes cells to alkylating agent-induced cytotoxicity. We recently demonstrated that this sensitivity is preceded by an increased production of AP sites and strand breaks, confirming that overexpression of MPG disrupts normal base excision repair and causes cell death through overproduction of toxic repair intermediates. Here we establish through site-directed mutagenesis that MPG-induced sensitivity to alkylation is dependent on enzyme glycosylase activity. However, in contrast to the sensitivity seen to heterogeneous alkylating agents, MPG overexpression generates no cellular sensitivity to MeOSO2(CH2)2-lexitropsin, an alkylator which exclusively induces 3-meA lesions. Indeed, MPG overexpression has been shown to increase the toxicity of alkylating agents that produce 7-meG adducts, and here we demonstrate that MPG-overexpressing cells have dramatically increased removal of 7-meG from their DNA. These data suggest that the mechanism of MPG-induced cytotoxicity involves the conversion of non-toxic 7-meG lesions into highly toxic repair intermediates. This study establishes a mechanism by which a benign DNA modification can be made toxic through the overexpression of an otherwise well-tolerated gene product, and the application of this principle could lead to improved chemotherapeutic strategies that reduce the peripheral toxicity of alkylating agents.


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