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

DNA polymerase η (Polη) is unique among eukaryotic DNA polymerases in its proficient ability to replicate through distorting DNA lesions, and Polη synthesizes DNA with a low fidelity. Here, we use pre-steady-state kinetics to investigate the mechanism of nucleotide incorporation by Polη and show that it utilizes an induced-fit mechanism to selectively incorporate the correct nucleotide. Polη 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 Polη to bypass lesions with distorted DNA geometries, and it bestows upon the enzyme a low fidelity.