Dividing the workload at a eukaryotic replication fork

Efficient and accurate replication of the eukaryotic nuclear genome requires DNA polymerases (Pols) α, δ and ɛ. In all current replication fork models, polymerase α initiates replication. However, several models have been proposed for the roles of Pol δ and Pol ɛ in subsequent chain elongation and the division of labor between these two polymerases is still unclear. Here, we revisit this issue, considering recent studies with diagnostic mutator polymerases that support a model wherein Pol ɛ is primarily responsible for copying the leading-strand template and Pol δ is primarily responsible for copying the lagging-strand template. We also review earlier studies in light of this model and then consider prospects for future investigations of possible variations on this simple division of labor.