The Pyrimidine Ring-opened Derivative of 1,N 6-Ethenoadenine Is Excised from DNA by theEscherichia coli Fpg and Nth Proteins

• Published in: The Journal of biological chemistry Vol. 276; no. 24; pp. 21821 - 21827
• Main Authors: Speina, Elz˙bieta, Cieśla, Jarosław M., Wójcik, Jacek, Bajek, Monika, Kuśmierek, Jarosław T., Tudek, Barbara
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 01-06-2001
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M100998200

It was previously shown that 1, N
6 -ethenoadenine (εA) in DNA rearranges into a pyrimidine ring-opened derivative of 20-fold higher mutagenic potency in Escherichia coli (AB1157 lac ΔU169) than the parental εA (Basu, A. K., Wood, M. L., Niedernhofer, L. J., Ramos, L. A., and Essigmann, J. M. (1993) Biochemistry 32, 12793–12801). We have found that at pH 7.0, the stability of the N -glycosidic bond in εdA is 20-fold lower than in dA. In alkaline conditions, but also at neutrality, εdA depurinates or converts
into products: εdA → B → C → D. Compound B is a product of water molecule addition to the C(2)–N(3) bond, which is in equilibrium
with a product of N(1)–C(2) bond rupture in εdA. Compound C is a deformylated derivative of ring-opened compound B, which
further depurinates yielding compound D. Ethenoadenine degradation products are not recognized by human N -alkylpurine-DNA glycosylase, which repairs εA. Product B is excised from oligodeoxynucleotides by E. coli formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease III (Nth). Repair by the Fpg protein is as efficient as that of
7,8-dihydro-8-oxoguanine when the excised base is paired with dT and dC but is less favorable when paired with dG and dA.
Ethenoadenine rearrangement products are formed in oligodeoxynucleotides also at neutral pH at the rate of about 2–3% per
week at 37 °C, and therefore they may contribute to εA mutations.