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Originally published In Press as doi:10.1074/jbc.M002441200 on July 6, 2000

J. Biol. Chem., Vol. 275, Issue 37, 28607-28617, September 15, 2000
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Substrate Specificity and Reaction Mechanism of Murine 8-Oxoguanine-DNA Glycosylase*

Dmitry O. ZharkovDagger §, Thomas A. Rosenquist||, Sue Ellen Gerchman**, and Arthur P. GrollmanDagger

From the Dagger  Laboratory of Chemical Biology, || Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794, § Novosibirsk Institute of Bioorganic Chemistry, Siberian Division of Russian Academy of Sciences, Prospect Lavrentieva 8, Novosibirsk 630090, Russia, and ** Biology Department, Brookhaven National Laboratory, Upton, New York 11973

Genomic DNA is prone to oxidation by reactive oxygen species. A major product of DNA oxidation is the miscoding base 8-oxoguanine (8-oxoG). The mutagenic effects of 8-oxoG in mammalian cells are prevented by a DNA repair system consisting of 8-oxoguanine-DNA glycosylase (Ogg1), adenine-DNA glycosylase, and 8-oxo-dGTPase. We have cloned, overexpressed, and characterized mOgg1, the product of the murine ogg1 gene. mOgg1 is a DNA glycosylase/AP lyase belonging to the endonuclease III family of DNA repair enzymes. The AP lyase activity of mOgg1 is significantly lower than its glycosylase activity. mOgg1 releases 8-oxoG from DNA when paired with C, T, or G, but efficient DNA strand nicking is observed only with 8-oxoG:C. Binding of mOgg1 to oligonucleotides containing 8-oxoG:C is strong (KD = 51.5 nM), unlike other mispairs. The average residence time for mOgg1 bound to substrate containing 8-oxoG:C is 18.3 min; the time course for accumulation of the NaBH4-sensitive intermediate suggests a two-step reaction mechanism. Various analogs of 8-oxoG were tested as substrates for mOgg1. An electron-withdrawing or hydrogen bond acceptor moiety at C8 is required for efficient binding of mOgg1. A substituent at C6 and a keto group at C8 are required for cleavage. The proposed mechanism of 8-oxoG excision involves protonation of O8 or the deoxyribose oxygen moiety.

* This work was supported by NCI, National Institutes of Health, Grant CA17395.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 631-444-3585; Fax: 631-444-7641; E-mail: dmitry@pharm.sunysb.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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