One of the major base lesions induced by oxidative stress is 8-oxoguanine (8-oxoG), one of the oxidised forms of guanine. 8-oxoguanine DNA glycosylase (also known as N-glycosylase/DNA lyase) functions in base excision repair and is responsible for the excision of 8-oxoguanine. It has beta-lyase activity thatnicks DNA 3' to the lesion [, , ].
This entry represents bifunctional, thermostable 8-oxoguanine DNA glycosylase/DNA lyase enzymes (OGG or OG glycosylases), which are involved in base excision repair of DNAdamaged by oxidation or by mutagenic agents []. Most damage to bases in DNA is repaired by the base excision repair pathway []. These enzymes have both DNA glycosylase activity () and AP lyase activity (). OGG1 enzymes are active only towards the removal of 8-oxoguanine [].
Oxidative damage represents a major threat to genomic stability, as the major product of DNA oxidation, 8-oxoguanine (GO), frequently mispairs with adenine during replication. In order to prevent these mutagenic events, organisms have evolved GO-DNA glycosylases (or N-glycosylase/DNA lyases) that remove this oxidized base from DNA []. GO is removed from DNA predominantly by the base excision repair (BER) pathway. This process is initiated by 8-oxoguanine-DNA glycosylases, which cleave the N-glycosidic bond between the aberrant base and the sugar-phosphate backbone to generate an apurinic (AP) site. Some DNA glycosylases possess also an intrinsic AP lyase activity, which cleaves the phosphodiester bond 3' from the AP site by beta- or beta, delta-elimination, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate [].This group represents archaeal GO-DNA glycosylases (AGOG). Pyrobaculum aerophilum PAE2237 has been shown to remove GO from single- and double-stranded substrates with great efficiency []. It has both GO-DNA glycosylase and AP-lyase () activities [].Archaeal GO-DNA glycosylases are not closely related to other DNA glycosylases. However, they share with the other HhH-GPD DNA glycosylase families the overall fold and the general active site architecture. AGOG possesses the principal hallmark of GO-DNA glycosylases: a helix-hairpin-helix motif and a glycine/proline-rich sequence followed by an absolutely conserved aspartate (HhH-GPD motif) []. It contains two α-helical subdomains, with the 8-oxoguanine binding site located in a cleft at their interface []. AGOG belongs to a new class within the helix-hairpin-helix (HhH) superfamily of DNA repair enzymes. Its hairpin structure differs substantially from that of other proteins containing an HhH motif, and is predicted that to interact with the DNA backbone in a distinct manner. Furthermore, the mode of 8-oxoguanine recognition, which involves several hydrogen-bonding and pi-stacking interactions, is unlike that observed in human OGG1, the prototypic 8-oxoguanine HhH-type DNA glycosylase. Despite these differences, the predicted kinked conformation of bound DNA and the catalytic mechanism are likely to resemble thoseof human OGG1 [].
