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| Subject Categories: Genome Stability & Dynamics |
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| The EMBO Journal
(2006) 25, 2189–2198, doi:10.1038/sj.emboj.7601109 Published online 27 April 2006 |
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| Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA |
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| Jeanette Ringvoll1, Line M Nordstrand1, Cathrine B Vågbø2, Vivi Talstad2, Karen Reite1, Per Arne Aas2, Knut H Lauritzen1, Nina Beate Liabakk2, Alexandra Bjørk1, Richard William Doughty3, Pål Ø Falnes1, 4, Hans E Krokan2 and Arne Klungland1, 5 |
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1 Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, Oslo, Norway 2 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 3 Department of Safety, PCS Biology, GE Healthcare Bio-sciences, Oslo, Norway 4 Department of Molecular Biosciences, University of Oslo, Oslo, Norway 5 Department of Nutrition, Institute of Basic Medical Science, University of Oslo, Oslo, Norway To whom correspondence should be addressed Arne Klungland, Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, 0027 Oslo, Norway. Tel.: +47 23074072; Fax: +47 23074061; E-mail: aklungla@medisin.uio.no Received 17 October 2005; Accepted 31 March 2006; Published online 27 April 2006. |
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| Abstract |
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| Two human homologs of the Escherichia coli AlkB protein, denoted hABH2 and hABH3, were recently shown to directly reverse 1-methyladenine (1meA) and 3-methylcytosine (3meC) damages in DNA. We demonstrate that mice lacking functional mABH2 or mABH3 genes, or both, are viable and without overt phenotypes. Neither were histopathological changes observed in the gene-targeted mice. However, in the absence of any exogenous exposure to methylating agents, mice lacking mABH2, but not mABH3 defective mice, accumulate significant levels of 1meA in the genome, suggesting the presence of a biologically relevant endogenous source of methylating agent. Furthermore, embryonal fibroblasts from mABH2-deficient mice are unable to remove methyl methane sulfate (MMS)-induced 1meA from genomic DNA and display increased cytotoxicity after MMS exposure. In agreement with these results, we found that in vitro repair of 1meA and 3meC in double-stranded DNA by nuclear extracts depended primarily, if not solely, on mABH2. Our data suggest that mABH2 and mABH3 have different roles in the defense against alkylating agents. |
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| Keywords: AlkB, DNA repair, knockout, mouse, oxidative demethylation |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSMolecular biology A fix for RNA Nature News and Views (20 Feb 2003) Nature Cell Biology News and Views (01 Mar 2003) RESEARCHCrystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB Nature Letters to Editor (16 Feb 2006) Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage The EMBO Journal Article (26 Jul 2006) |
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