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Originally published In Press as doi:10.1074/jbc.M010641200 on January 22, 2001

J. Biol. Chem., Vol. 276, Issue 16, 13379-13387, April 20, 2001
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Base Excision and DNA Binding Activities of Human Alkyladenine DNA Glycosylase Are Sensitive to the Base Paired with a Lesion*

Clint W. AbnerDagger , Albert Y. Lau§, Tom Ellenberger§, and Linda B. BloomDagger

From the Dagger  Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610-0245 and the § Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

The human alkyladenine DNA glycosylase has a broad substrate specificity, excising a structurally diverse group of damaged purines from DNA. To more clearly define the structural and mechanistic bases for substrate specificity of human alkyladenine DNA glycosylase, kinetics of excision and DNA binding activities were measured for several different damaged and undamaged purines within identical DNA sequence contexts. We found that 1,N6-ethenoadenine (epsilon A) and hypoxanthine (Hx) were excised relatively efficiently, whereas 7,8-dihydro-8-oxoguanine, O6-methylguanine, adenine, and guanine were not. Single-turnover kinetics of excision of Hx and epsilon A paired with T showed that excision of Hx was about four times faster than epsilon A, whereas binding assays showed that the binding affinity was about five times greater for epsilon A than for Hx. The opposing pyrimidine base had a significant effect on the kinetics of excision and DNA binding affinity of Hx but a small effect on those for epsilon A. Surprisingly, replacing a T with a U opposite Hx dramatically reduced the excision rate by a factor of 15 and increased the affinity by a factor of 7-8. The binding affinity of human alkyladenine DNA glycosylase to a DNA product containing an abasic site was similar to that for an Hx lesion.

* This work was supported by a National Science Foundation Grant MCB-0096197 (to L. B. B.), by a grant from the NIGMS, National Institutes of Health (NIH) (to T. E.), and by a training grant from the NIEHS, NIH (to A.Y.L.).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.: 352-392-8708; Fax: 352-392-1445; E-mail: lbloom@ufl.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.