réplisomes

Replisomes are multi-protein complexes that assemble at DNA replication forks to carry out DNA replication. They coordinate helicase-driven unwinding with primer synthesis, leading-strand synthesis, and lagging-strand synthesis while processing RNA primers and nicks.

In bacteria, the replisome centers on a DnaB helicase with the DnaG primase, the DNA polymerase III holoenzyme as the main replicative polymerase, the beta sliding clamp and the gamma complex clamp loader, and auxiliary factors such as single-stranded DNA-binding protein (SSB) and topoisomerases. In archaea and eukaryotes, replication involves the CMG helicase (Cdc45–MCM2–7–GINS) together with DNA polymerases alpha-primase for primer synthesis and polymerases delta and epsilon for DNA synthesis, aided by PCNA sliding clamps and RFC clamp loaders. RPA protects single-stranded DNA, and topoisomerases relieve supercoiling.

Mechanism: The helicase opens the double helix at the fork; primers are laid for discontinuous lagging-strand synthesis. The leading strand is synthesized continuously by a high-processivity polymerase, while the lagging strand is synthesized as Okazaki fragments that are later processed and joined. The trombone model describes the looping of the lagging strand to coordinate synthesis with the leading strand.

Regulation: Replisome assembly is tightly controlled during the cell cycle and origin-specific initiation. In bacteria, DnaA initiates origin melting with helicase loading; in eukaryotes, origin licensing by ORC/Cdc6/Cdt1 creates MCM2-7 hexamers that are activated to form the CMG complex in S phase.

Significance: Proper replisome function is essential for genome stability; replication stress or defects can contribute to disease and are targets for therapeutic intervention.