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

Abstract

Endogenous formation of the mutagenic DNA adduct 1,N 6 -ethenoadenine (EA) originates from lipid peroxidation. Elevated levels of EA 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 EA 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 EA lesions in DNA. Furthermore, cation exchange chromatography of nuclear extracts from wild-type and mABH2 À/À mice indicates that mABH2 is the principal dioxygenase for EA 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 EA lesions, and that ABH2, together with the alkyl-N-adenine-DNA glycosylase, which is the most effective enzyme for the repair of EA, comprise the cellular defense against EA lesions. [Cancer Res 2008;68(11):4142-9]

The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

“…Recently, another direct reversal pathway mediated by ABH2 dioxygenase has been identified in mammalian cells (Ringvoll et al 2008). This protein can directly repair 1,N 6 -ethenoadenine adducts in nDNA in an iron, oxoglutarate-dependent manner.…”

TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish

“…Finally the apex1 gene which is a component of the base excision repair mechanism, 48 xrcc5 which repairs double strand breaks in zebrafish embryos, 49 and the alkbh2 gene which is involved in repairing DNA etheno adducts, 50 were upregulated ( Table 1). Gadd45 proteins are involved in cell-cycle regulation and are normally induced by genome damage and stress conditions, and regulate somite formation in zebrafish.…”

Damage of DNA and proteins by major lipid peroxidation products in genome stability

“…eliminates also εA from ds and ssDNA [117], and thus may be a backup enzyme for ANPG glycosylase. Recently, it was shown that hABH2 repairs εC, as well, and probably competes with ANPG in the access to the lesion, since ANPG inhibits in vitro repair of εC by ABH2 [118].…”