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J. Biol. Chem., Vol. 282, Issue 21, 15790-15798, May 25, 2007

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Human Polymorphic Variants of the NEIL1 DNA Glycosylase^*

Laura M. Roy¹, Pawel Jaruga^¶1, Thomas G. Wood^||, Amanda K. McCullough, Miral Dizdaroglu^**, and R. Stephen Lloyd²

From the Center for Research on Occupational and Environmental Toxicology, Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97239-3098, Department of Chemical and Biochemical Engineering, University of Maryland Baltimore County, Baltimore, Maryland 21250; ^¶Department of Clinical Biochemistry, Collegium Medicum, Nicolaus Copernicus University, 85-092 Bydgoszcz, Poland, ^||Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-1071, and ^**Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899-8311

In mammalian cells, the repair of DNA bases that have been damaged by reactive oxygen species is primarily initiated by a series of DNA glycosylases that include OGG1, NTH1, NEIL1, and NEIL2. To explore the functional significance of NEIL1, we recently reported that neil1 knock-out and heterozygotic mice develop the majority of symptoms of metabolic syndrome (Vartanian, V., Lowell, B., Minko, I. G., Wood, T. G., Ceci, J. D., George, S., Ballinger, S. W., Corless, C. L., McCullough, A. K., and Lloyd, R. S. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 1864-1869). To determine whether this phenotype could be causally related to human disease susceptibility, we have characterized four polymorphic variants of human NEIL1. Although three of the variants (S82C, G83D, and D252N) retained near wild type levels of nicking activity on abasic (AP) site-containing DNA, G83D did not catalyze the wild type ,-elimination reaction but primarily yielded the -elimination product. The AP nicking activity of the C136R variant was significantly reduced. Glycosylase nicking activities were measured on both thymine glycol-containing oligonucleotides and -irradiated genomic DNA using gas chromatography/mass spectrometry. Two of the polymorphic variants (S82C and D252N) showed near wild type enzyme specificity and kinetics, whereas G83D was devoid of glycosylase activity. Although insufficient quantities of C136R could be obtained to carry out gas chromatography/mass spectrometry analyses, this variant was also devoid of the ability to incise thymine glycol-containing oligonucleotide, suggesting that it may also be glycosylase-deficient. Extrapolation of these data suggests that individuals who are heterozygous for these inactive variant neil1 alleles may be at increased risk for metabolic syndrome.

Received for publication, November 15, 2006 , and in revised form, February 15, 2007.

^* This work was supported in part by National Institutes of Health Grants DK075974 and ES06676, the Houston Endowment, and the Oregon Opportunity Fund. 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 contributed equally to this work.

² To whom correspondence should be addressed: Center for Research on Occupational and Environmental Toxicology L606, Dept. of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098. Tel.: 503-494-9957; E-mail: lloydst{at}ohsu.edu.

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