The CMG DNA helicase and the core replisome

Eukaryotic DNA replication is performed by the replisome, a large and dynamic multi-protein machine endowed with the required enzymatic components for the synthesis of new DNA. Recent cryo-electron microscopy (cryoEM) analyses have revealed the conserved architecture of the core eukaryotic replisome, comprising the CMG (Cdc45-MCM-GINS) DNA helicase, the leading-strand DNA polymerase epsilon, the Timeless-Tipin heterodimer, the hub protein AND-1 and the checkpoint protein Claspin. These results bid well for arriving soon at an integrated understanding of the structural basis of semi-discontinuous DNA replication. They further set the scene for the characterisation of the mechanisms that interface DNA synthesis with concurrent processes such as DNA repair, propagation of chromatin structure and establishment of sister chromatid cohesion. •The core architecture of the eukaryotic replisome is built around the CMG DNA helicase and is conserved from yeast to humans.•The CMG helicase adopts an asymmetric rotary mode of DNA translocation that reflects the heteromeric ring of MCM2-7 ATPases.•The CMG helicase separates the strands of the parental DNA by a version of the steric exclusion mechanism.•Pol epsilon C-end binds the CMG trailing edge and its N-end engages the emerging leading-strand template for DNA synthesis.•In the replisome, Timeless and AND-1 are poised to engage with parental DNA and other replication factors ahead of the fork.