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J. Biol. Chem., Vol. 282, Issue 30, 21913-21923, July 27, 2007

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Induction of Base Damages Representing a High Risk Site for Double-strand DNA Break Formation in Genomic DNA by Exposure of Cells to DNA Damaging Agents^*

From the Division of Health and Environmental Research, Laval University Medical Centre (CHUL) and Department of Anatomy and Physiology, Faculty of Medicine, Laval University, 2705 Boulevard Laurier, Quebec, Quebec G1V 4G2, Canada

DNA repair is known as a defense mechanism against genotoxic insults. However, the most lethal type of DNA damages, double-strand DNA breaks (DSBs), can be produced by DNA repair. We have previously demonstrated that when long patch base excision repair attempts to repair a synthetic substrate containing two uracils, the repair produces DSBs (Vispe, S. and Satoh, M. S. (2000) J. Biol. Chem. 275, 27386-27392 and Vispe, S., Ho, E. L., Yung, T. M., and Satoh, M. S. (2003) J. Biol. Chem. 278, 35279-35285). In this synthetic substrate, the two uracils are located on the opposite DNA strands (separated by an intervening sequence stable at 37 °C) and represent a high risk site for DSB formation. It is not clear, however, whether similar high risk sites are also induced in genomic DNA by exposure to DNA damaging agents. Thus, to investigate the mechanisms of DSB formation, we have modified the DSB formation assay developed previously and demonstrated that high risk sites for DSB formation are indeed generated in genomic DNA by exposure of cells to alkylating agents. In fact, genomic DNA containing alkylated base damages, which could represent high risk sites, are converted into DSBs by enzymes present in extracts prepared from cells derived from clinically normal individuals. Furthermore, DSBs are also produced by extracts from cells derived from ataxia-telangiectasia patients who show cancer proneness due to an impaired response to DSBs. These results suggest the presence of a novel link between base damage formation and DSBs and between long patch base excision repair and human diseases that occur due to an impaired response to DSB.

Received for publication, November 16, 2006 , and in revised form, April 16, 2007.

^* This work was supported by the Canadian Institutes of Health Research and Canadian Breast Cancer Research Alliance. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors equally contributed to this work.

² To whom correspondence should be addressed. Tel.: 418-656-4141 (ext. 47340); Fax: 418-654-2159; E-mail: masahiko.sato{at}crchul.ulaval.ca.

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