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J. Biol. Chem., Vol. 279, Issue 18, 18425-18433, April 30, 2004

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Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase -Dependent Base Excision Repair^*

Julian J. Raffoul, Diane C. Cabelof, Jun Nakamura, Lisiane B. Meira¶||, Errol C. Friedberg¶, and Ahmad R. Heydari**

From the Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan 48202, the Department of Environmental Sciences and Engineering, the University of North Carolina, Chapel Hill, North Carolina 27599, and ^¶Laboratory of Molecular Pathology, Department of Pathology, the University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072

Apurinic/apyrimidinic (AP) endonuclease (APE) is a multifunctional protein possessing both DNA repair and redox regulatory activities. In base excision repair (BER), APE is responsible for processing spontaneous, chemical, or monofunctional DNA glycosylase-initiated AP sites via its 5'-endonuclease activity and 3'-"end-trimming" activity when processing residues produced as a consequence of bifunctional DNA glycosylases. In this study, we have fully characterized a mammalian model of APE haploinsufficiency by using a mouse containing a heterozygous gene-targeted deletion of the APE gene (Apex^+/–). Our data indicate that Apex^+/– mice are indeed APE-haploinsufficient, as exhibited by a 40–50% reduction (p < 0.05) in APE mRNA, protein, and 5'-endonuclease activity in all tissues studied. Based on gene dosage, we expected to see a concomitant reduction in BER activity; however, by using an in vitro G:U mismatch BER assay, we observed tissue-specific alterations in monofunctional glycosylase-initiated BER activity, e.g. liver (35% decrease, p < 0.05), testes (55% increase, p < 0.05), and brain (no significant difference). The observed changes in BER activity correlated tightly with changes in DNA polymerase and AP site DNA binding levels. We propose a mechanism of BER that may be influenced by the redox regulatory activity of APE, and we suggest that reduced APE may render a cell/tissue more susceptible to dysregulation of the polymerase -dependent BER response to cellular stress.

Received for publication, December 22, 2003 , and in revised form, February 12, 2004.

^* This work was supported by National Institutes of Health Grant 1R21-DK62256 and American Institute for Cancer Research Grant 03A061. 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.

^|| Present address: Division of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.

^** To whom correspondence should be addressed: Dept. of Nutrition and Food Science, 3009 Science Hall, Wayne State University, Detroit, MI 48202. Tel.: 313-577-2427; Fax: 313-577-8616; E-mail: ahmad.heydari{at}wayne.edu.

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