Human Polymorphic Variants of the NEIL1 DNA Glycosylase
| Autor: | Miral Dizdaroglu, Laura M. Roy, Amanda K. McCullough, Pawel Jaruga, Thomas G. Wood, R. Stephen Lloyd |
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| Rok vydání: | 2007 |
| Předmět: |
DNA Repair
Mutation Missense NEIL1 Biology medicine.disease_cause Biochemistry DNA Glycosylases Deoxyribonuclease (Pyrimidine Dimer) Mice chemistry.chemical_compound DNA-(Apurinic or Apyrimidinic Site) Lyase medicine Animals Humans Genetic Predisposition to Disease Molecular Biology Metabolic Syndrome Mice Knockout Genetics Mutation Polymorphism Genetic Oligonucleotide Wild type Cell Biology Molecular biology Thymine Kinetics genomic DNA Amino Acid Substitution Oligodeoxyribonucleotides chemistry Gamma Rays DNA glycosylase DNA |
| Zdroj: | Journal of Biological Chemistry. 282:15790-15798 |
| ISSN: | 0021-9258 |
| Popis: | 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 beta,delta-elimination reaction but primarily yielded the beta-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 gamma-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. |
| Databáze: | OpenAIRE |
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