Yeast DNA polymerase η utilizes an induced-fit mechanism of nucleotide incorporation

DNA polymerase eta (Pol eta) is unique among eukaryotic DNA polymerases in its proficient ability to replicate through distorting DNA lesions, and Pol eta synthesizes DNA with a low fidelity. Here, we use pre-steady-state kinetics to investigate the mechanism of nucleotide incorporation by Pol eta and show that it utilizes an induced-fit mechanism to selectively incorporate the correct nucleotide. Pol eta discriminates poorly between the correct and incorrect nucleotide at both the initial nucleotide binding step and at the subsequent induced-fit conformational change step, which precedes the chemical step of phosphodiester bond formation. This property enables Pol eta to bypass lesions with distorted DNA geometries, and it bestows upon the enzyme a low fidelity.