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AlkB Homologue 2–Mediated Repair of Ethenoadenine Lesions in Mammalian DNA

¹ Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Rikshospitalet HF and University of Oslo, ² Department of Molecular Biosciences, University of Oslo, Blindern, Oslo, Norway; ³ Faculty of Science and Technology, Department of Mathematics and Natural Sciences, University of Stavanger, Stavanger, Norway; and ⁴ Biological Engineering Department, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts

Requests for reprints: Arne Klungland, Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Sognsvannsveien 20, Oslo 0027, Norway. Phone: 47-2307-4072; Fax: 47-2307-4061; E-mail: aklungla{at}medisin.uio.no.

Key Words: DNA repair • ABH2 • AlkB • ethenoadenine

Endogenous formation of the mutagenic DNA adduct 1,N⁶-ethenoadenine (A) originates from lipid peroxidation. Elevated levels of A in cancer-prone tissues suggest a role for this adduct in the development of some cancers. The base excision repair pathway has been considered the principal repair system for A lesions until recently, when it was shown that the Escherichia coli AlkB dioxygenase could directly reverse the damage. We report here kinetic analysis of the recombinant human AlkB homologue 2 (hABH2), which is able to repair A lesions in DNA. Furthermore, cation exchange chromatography of nuclear extracts from wild-type and mABH2^–/– mice indicates that mABH2 is the principal dioxygenase for A repair in vivo. This is further substantiated by experiments showing that hABH2, but not hABH3, is able to complement the E. coli alkB mutant with respect to its defective repair of etheno adducts. We conclude that ABH2 is active in the direct reversal of A lesions, and that ABH2, together with the alkyl-N-adenine-DNA glycosylase, which is the most effective enzyme for the repair of A, comprise the cellular defense against A lesions. [Cancer Res 2008;68(11):4142–9]

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