Article
- The EMBO Journal (2006) 25, 2189 - 2198
- doi:10.1038/sj.emboj.7601109
Published online: 27 April 2006
Subject Category:
Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA
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
- Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, Oslo, Norway
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim
- Department of Safety, PCS Biology, GE Healthcare Bio-sciences, Oslo, Norway
- Department of Molecular Biosciences, University of Oslo, Oslo, Norway
- Department of Nutrition, Institute of Basic Medical Science, University of Oslo, Oslo, Norway
Correspondence to:
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
Abstract
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.
Keywords:
- AlkB,
- DNA repair,
- knockout,
- mouse,
- oxidative demethylation
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