Structural basis of high fidelity DNA synthesis by yeast DNA polymerase delta

DNA polymerase δ (Polδ) is a high fidelity polymerase that plays a central role in replication from yeast to humans. We present here the crystal structure of the catalytic subunit of yeast Polδ in ternary complex with a template-primer and an incoming nucleotide. The structure, determined at 2.0Å resolution, catches the enzyme in the act of replication. The structure reveals how the polymerase and exonuclease domains are juxtaposed relative to each other and how a correct nucleotide is selected and incorporated. The structure also reveals the “sensing” interactions near the primer terminus that signal a switch from the polymerizing to the editing mode. Taken together, the structure provides a chemical basis for the bulk of DNA synthesis in eukaryotic cells and a framework for understanding the effects of mutations in Polδ̣ that cause cancers.