A Major Role of DNA Polymerase δ in Replication of Both the Leading and Lagging DNA Strands

Genetic studies with S. cerevisiae Polδ (pol3-L612M) and Polε (pol2-M644G) mutant alleles, each of which display a higher rate for the generation of a specific mismatch, have led to the conclusion that Polε is the primary leading strand replicase and that Polδ is restricted to replicating the lagging strand template. Contrary to this widely accepted view, here we show that Polδ plays a major role in the replication of both DNA strands, and that the paucity of pol3-L612M-generated errors on the leading strand results from their more proficient removal. Thus, the apparent lack of Polδ contribution to leading strand replication is due to differential mismatch removal rather than differential mismatch generation. Altogether, our genetic studies with Pol3 and Pol2 mutator alleles support the conclusion that Polδ, and not Polε, is the major DNA polymerase for carrying out both leading and lagging DNA synthesis. [Display omitted] •Polδ-generated errors occur on both the leading and lagging DNA strands•Polδ errors are removed by mismatch repair, Polε exonuclease, and Exo1•Polδ replicates both the leading and lagging DNA strands•Polε does not replicate the leading strand The current model of eukaryotic DNA replication suggests that DNA polymerase (Pol)ε primarily replicates the leading strand while Polδ replicates the lagging strand. Johnson et al. provide genetic evidence that Polδ replicates both strands, while Polε’s proofreading activity is important for removing Polδ-generated errors from the leading strand.