Arranging eukaryotic nuclear DNA polymerases for replication

Biochemical and cryo-electron microscopy studies have just been published revealing interactions among proteins of the yeast replisome that are important for highly coordinated synthesis of the two DNA strands of the nuclear genome. These studies reveal key interactions important for arranging DNA polymerases α, δ, and ϵ for leading and lagging strand replication. The CMG (Mcm2-7, Cdc45, GINS) helicase is central to this interaction network. These are but the latest examples of elegant studies performed in the recent past that lead to a much better understanding of how the eukaryotic replication fork achieves efficient DNA replication that is accurate enough to prevent diseases yet allows evolution.

Priming of the leading strands in this model is carried out by two CMG-Pol ϵ-Pol α complexes (CMG = Cdc45-Mcm2-7-GINS) bound to opposite strands at a replication origin. As each CMG helicase moves in the direction of the fork, Pol α bound to the N-terminal domain of CMG synthesizes a short RNA–DNA primer. This primer is captured and elongated by Pol δ (top panel, in blue). When the faster moving Pol δ complex collides with the slower moving CMG-Pol ϵ complex, Pol δ is released and Pol ϵ engages with the elongated primer to perform the bulk of leading-strand DNA replication (green).

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