N-glycosyl bond formation catalyzed by human alkyladenine DNA glycosylase.

ABSTRACT

The removal of damaged bases by DNA glycosylases is thought to be effectively irreversible, because of an overall equilibrium that favors hydrolysis over synthesis of the N-glycosyl bond. Surprisingly, human alkyladenine DNA glycosylase (AAG) can make damaged DNA by catalyzing formation of an N-glycosyl bond between 1,N(6)-ethenoadenine (εA) and abasic DNA. We attribute the ready reversibility of this glycosylase reaction to the exceptionally tight binding and slow subsequent hydrolysis of DNA containing an εA lesion. In principle, reversibility could provide a mechanism for direct reversal of base damage by a DNA glycosylase, allowing the glycosylase to bypass the rest of the base excision repair pathway.