The promutagenic and genotoxic exocyclic DNA adduct 1,N(2)-ethenoguanine 
(1,N(2)-epsilonG) is a major product formed in DNA exposed to lipid 
peroxidation-derived aldehydes in vitro. Here, we report that two structurally 
unrelated proteins, the Escherichia coli mismatch-specific uracil-DNA 
glycosylase (MUG) and the human alkylpurine-DNA-N-glycosylase (ANPG), can 
release 1,N(2)-epsilonG from defined oligonucleotides containing a single 
modified base. A comparison of the kinetic constants of the reaction indicates 
that the MUG protein removes the 1,N(2)-epsilonG lesion more efficiently 
(k(cat)/K(m) = 0.95 x 10(-3) min(-1) nm(-1)) than the ANPG protein (k(cat)/K(m) 
= 0.1 x 10(-3) min(-1) nm(-1)). Additionally, while the nonconserved, N-terminal 
73 amino acids of the ANPG protein are not required for activity on 
1,N(6)-ethenoadenine, hypoxanthine, or N-methylpurines, we show that they are 
essential for 1,N(2)-epsilonG-DNA glycosylase activity. Both the MUG and ANPG 
proteins preferentially excise 1,N(2)-epsilonG when it is opposite dC; however, 
unlike MUG, ANPG is unable to excise 1,N(2)-epsilonG when it is opposite dG. 
Using cell-free extracts from genetically modified E. coli and murine embryonic 
fibroblasts lacking MUG and mANPG activity, respectively, we show that the 
incision of the 1,N(2)-epsilonG-containing duplex oligonucleotide has an 
absolute requirement for MUG or ANPG. Taken together these observations suggest 
a possible role for these proteins in counteracting the genotoxic effects of 
1,N(2)-epsilonG residues in vivo.