DNA polymerase δ proofreads errors made by DNA polymerase e

During eukaryotic replication, DNA polymerases e (Pole) and δ (Polδ) synthesize the leading and lagging strands, respectively. In a long-known contradiction to this model, defects in the fidelity of Pole have a much weaker impact on mutagenesis than analogous Polδ defects. It has been previously proposed that Polδ contributes more to mutation avoidance because it proofreads mismatches created by Pole in addition to its own errors. However, direct evidence for this model was missing. We show that, in yeast, the mutation rate increases synergistically when a Pole nucleotide selectivity defect is combined with a Polδ proofreading defect, demonstrating extrinsic proofreading of Pole errors by Polδ. In contrast, combining Polδ nucleotide selectivity and Pole proofreading defects produces no synergy, indicating that Pole cannot correct errors made by Polδ. We further show that Polδ can remove errors made by exonuclease-deficient Pole in vitro. These findings illustrate the complexity of the one-strand-one-polymerase model where synthesis appears to be largely divided, but Polδ proofreading operates on both strands.