Imagine pol as Thing of the Addams Family, an enzyme hand that moves along the DNA strand searching for the remnants of a base that has been damaged by anything from oxidation to ultraviolet radiation. When discovered, the damaged base and the residue it leaves behind are excised by other enzymes. Pol then moves in and fills the gap with the appropriate base. It closes around the gap like a fist and traps together the new base, the template DNA, and the catalyst used by the enzyme to start the reaction that bonds the two backbones connecting the bases. Once the new base has been secured, the polymerase reopens and moves on.

An array of amino acids make up the fingers of the polymerase and control interactions between the base coming in to repair the gap and the base on the template strand. The enzyme hand's palm plays a role in catalysis. These features are almost entirely inflexible as the polymerase goes from open to closed to open again. The thumb, meanwhile, is responsible for most of the motion, closing toward the palm and rotating inward. It likely plays an important role in positioning the DNA and incoming base so they can bind.

This "induced fit" mechanism by which the thumb moves and the polymerase changes shape is thought to occur correctly only when proper base complements are matched to one another. Linking adenine to thymine, for example, causes the fist to close, and the two bases are married in a tight fit. If adenine and guanine are inadvertently brought together, however, the closing process may be altered, so that the bases cannot properly align for replication to continue.

The shift that the polymerase undergoes is a fundamental element in replication fidelity. With a clear picture of this shift, researchers will better understand how pol ensures fidelity as well as what goes wrong when the fidelity machinery fails.