The structure and functions of the HAP1/Ref-1 protein

The HAP1/Ref-1 (hereafter referred to as HAP1) protein is a nuclear enzyme that apparently performs two distinct roles in the cellular defense against oxidative stress. One well-established role is in the repair of a variety of lesions induced in DNA either by spontaneous hydrolysis or by reactive oxygen species (ROS). This function has been characterized in great detail and the roles played by individual active site amino acid residues have been defined. The second role, which was identified only relatively recently and is still not characterized in detail, is to regulate the DNA binding activity of a group of nuclear factors. This second role proceeds via the modification of the oxidation/reduction (redox) state of a cysteine residue in the target protein, although the mechanism by which this is achieved remains to be elucidated. In this article, we shall review the latest knowledge on the relationship between structure and the dual functions of HAP1, and we will seek to explain in detail the roles played by several individual amino acid residues in the catalytic function of the HAP1 protein.