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J. Biol. Chem., Vol. 280, Issue 49, 40544-40551, December 9, 2005

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Repair of Formamidopyrimidines in DNA Involves Different Glycosylases

ROLE OF THE OGG1, NTH1, AND NEIL1 ENZYMES^*

Jingping Hu1, Nadja C. de Souza-Pinto1, Kazuhiro Haraguchi, Barbara A. Hogue, Pawel Jaruga¶||, Marc M. Greenberg, Miral Dizdaroglu¶, and Vilhelm A. Bohr2

From the Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224, the Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, the ^¶Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, and the ^||Department of Chemical and Biochemical Engineering, University of Maryland Baltimore County, Baltimore, Maryland 21250

The oxidatively induced DNA lesions 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 4,6-diamino-5-formamidopyrimidine (FapyA) are formed abundantly in DNA of cultured cells or tissues exposed to ionizing radiation or to other free radical-generating systems. In vitro studies indicate that these lesions are miscoding, can block the progression of DNA polymerases, and are substrates for base excision repair. However, no study has yet addressed how these lesions are metabolized in cellular extracts. The synthesis of oligonucleotides containing FapyG and FapyA at defined positions was recently reported. These constructs allowed us to investigate the repair of Fapy lesions in nuclear and mitochondrial extracts from wild type and knock-out mice lacking the two major DNA glycosylases for repair of oxidative DNA damage, OGG1 and NTH1. The background level of FapyG/FapyA in DNA from these mice was also determined. Endogenous FapyG levels in liver DNA from wild type mice were significantly higher than 8-hydroxyguanine levels. FapyG and FapyA were efficiently repaired in nuclear and mitochondrial extracts from wild type animals but not in the glycosylase-deficient mice. Our results indicated that OGG1 and NTH1 are the major DNA glycosylases for the removal of FapyG and FapyA, respectively. Tissue-specific analysis suggested that other DNA glycosylases may contribute to FapyA repair when NTH1 is poorly expressed. We identified NEIL1 in liver mitochondria, which could account for the residual incision activity in the absence of OGG1 and NTH1. FapyG and FapyA levels were significantly elevated in DNA from the knock-out mice, underscoring the biological role of OGG1 and NTH1 in the repair of these lesions.

Received for publication, August 9, 2005 , and in revised form, October 7, 2005.

^* This work was in part supported by National Institutes of Health Grant CA-074954 (to M. M. G.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental method and five supplemental figures.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Laboratory of Molecular Gerontology, NIA-IRP, National Institutes of Health, Box1, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8162; Fax: 410-558-8157; E-mail: vbohr{at}nih.gov.

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