Deoxyribose phosphate excision by the N-terminal domain of the polymerase beta: the mechanism revisited.

DNA polymerase beta (Pol beta) is one of the key enzymes in the base excision repair pathway. The amino-terminal 8 kDa domain of Pol beta has an activity for excising a 5'-deoxyribose phosphate (dRP) group from preincised apurine/apyrimidine (AP) sites. Recent biochemical studies have identified the catalytic center of the 8 kDa domain and provided new insight into the mechanism of DNA repair by DNA polymerase beta. By incorporating both structural and biochemical data, we present here a reaction mechanism for the 5'-dRP excision activity of the 8 kDa domain. This mechanism focuses on a catalytic groove near the helix-hairpin-helix (HhH) motif of the 8 kDa domain. Our model shows that the dRP group of the AP site can be stabilized in the catalytic groove through extensive interactions with the residues of the groove and be positioned close to the active center, Lys72, which catalyzes a beta-elimination reaction by forming a Schiff base with the C1' of the dRP group.