DNA polymerases that propagate the eukaryotic DNA replication fork

Three DNA polymerases are thought to function at the eukaryotic DNA replication fork. Currently, a coherent model has been derived for the composition and activities of the lagging strand machinery. RNA-DNA primers are initiated by DNA polymerase alpha-primase. Loading of the proliferating cell nuclear antigen, PCNA, dissociates DNA polymerase alpha and recruits DNA polymerase alpha and the flap endonuclease FEN1 for elongation and in preparation for its requirement during maturation, respectively. Nick transation by the strand displacement action of DNA polymerase delta, coupled with the nuclease action of FEN1, results in processive RNA degradation until a proper DNA nick is reached for closure by DNA ligase I. In the event of excessive strand displacement synthesis, other factors, such as the Dna2 nuclease/helicase, are required to trim excess flaps. Paradoxically, the composition and activity of the much simpler leading strand machinery has not been clearly established. The burden of evidence suggests that DNA polymerase epsilon normally replicates this strand, but under conditions of dysfunction, DNA polymerase delta may substitute.