PROSITE documentation PDOC00956

Formamidopyrimidine-DNA glycosylase signature and profiles

Most damage to bases in DNA is repaired by the base excision repair pathway [1]. The repair is initiated by DNA glycosylases, enzymes that recognize specific lesion bases in DNA and remove them. Formamidopyrimidine-DNA glycosylase (EC 3.2.2.23) (gene fpg) [2] is a bacterial DNA glycosylase that recognizes and removes damaged bases with a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG). Excision of the oxidized guanine occurs via nucleophilic substitution at C1' by the N-terminal proline . The aminal intermediate thus formed rearranges to the Schiff base, which subsequently undergoes β- and delta-elimination, resulting in complete removal of the lesion nucleoside from DNA. FPG has thus also a nicking activity that cleaves both the 3'- and 5'-phosphodiester bonds at the apurinic/apyrimidinic (AP) site, leaving a gap in the DNA that has phosphate groups on both the 5'- and 3'-ends [3].

The protein contains three structural domains: an N-terminal catalytic core domain, a central helix-two turn-helix (H2TH) module and a C-terminal zinc finger (see <PDB:1K82>) [4]. The N-terminal catalytic domain and the C-terminal zinc finger straddle the DNA with the long axis of the protein oriented roughly orthogonal to the helical axis of the DNA. Residues that contact DNA are located in the catalytic domain and in a β-hairpin loop formed by the zinc finger [5].

Endonuclease VIII (EC 3.2.-.-) (gene nei) is a DNA N-glycosylase with an AP lyase activity. It is evolutionary related to FPG. Orthologs of FPG have also been discovered in mammals (NEIL1, 2 AND 3). NEILs are also active in excising a variety of oxidatively damaged bases but show significant differences in substrate preference [6].

We have developed a signature pattern that covers the four conserved cysteines of the zinc finger, and, two profiles that span the entire catalytic domain and zinc finger.