Human Polymorphic Variants of the NEIL1 DNA Glycosylase: Potential Implications for Human Health

Published

May 25, 2007

Author(s)

Laura Roy, Pawel Jaruga, Thomas Wood, Amanda K. McCullough, M Miral Dizdar, R. S. Lloyd

Abstract

In mammalian cells, the repair of DNA bases 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 knockout and heterozygotic mice develop the majority of symptoms of the Metabolic Syndrome (Vartanian et al., Proceedings of the National Academy of Sciences, USA, 103, 1864-1869, 2006). As a first step in determining whether the phenotype observed in these mice could be causally related to human disease susceptibility, we have characterized four known polymorphic variants of human NEIL1. While three of the variants (S82C, G83D, D252N) retained near wild-type levels of nicking activity on abasic site (AP)-containing DNA, G83D did not catalyze the wild-type b-d-elimination reaction, but primarily yielded the b-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 (GC/MS). Two of the polymorphic variants (S82C and D252N) showed near wild-type enzyme specificity and kinetics, while G83D was devoid in glycosylase activity. Although insufficient quantities of C136R could be obtained to carry out GC/MS 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 diseases associated with the Metabolic Syndrome.

Citation

Journal of Biological Chemistry

Volume

282

Issue

21

Pub Type

Journals

Keywords

formamidopyrimidines, GC/MS, metabolic syndrome, oxidative DNA damage, polymorphism

Citation

Roy, L. , Jaruga, P. , Wood, T. , McCullough, A. , , M. and Lloyd, R. (2007), Human Polymorphic Variants of the NEIL1 DNA Glycosylase: Potential Implications for Human Health, Journal of Biological Chemistry (Accessed April 19, 2024)