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

Genetic studies with S. cerevisiae Pol delta (pol3-L612M) and Pol epsilon (pol2-M644G) mutant alleles, each of which display a higher rate for the generation of a specific mismatch, have led to the conclusion that Pol epsilon is the primary leading strand replicase and that Pol delta is restricted to replicating the lagging strand template. Contrary to this widely accepted view, here we show that Pol delta 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 Pol delta 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 Pol delta, and not Pol epsilon, is the major DNA polymerase for carrying out both leading and lagging DNA synthesis.