DNA replication: a complex matter

Abstract

In eukaryotic cells, the essential function of DNA replication is carried out by a network of enzymes and proteins, which work together to rapidly and accurately duplicate the genetic information of the cell. Many of the components of this DNA replication apparatus associate with other cellular factors as components of multiprotein complexes, which act cooperatively in networks to regulate cell cycle progression and checkpoint control, but are distinct from the pre-replication complexes that associate with the origins and regulate their firing. In this review, we summarize current knowledge about the composition and dynamics of these large multiprotein complexes in mammalian cells and their relationships to the replication factories.

Figure 1

Model of a DNA replication factory. This shows five activated replicons in a single factory (shaded area). Each replicon contains a replication bubble and two replication forks. At each fork, a DNA synthesome (dark grey circle) is bound to DNA and contains all the proteins required for DNA synthesis, including proliferating cell nuclear antigen (PCNA; not shown). However, additional replication factors (coloured symbols) accumulate in the factory in the vicinity of the replicons, as they bind to PCNA trimers (hexagons) that are not associated directly with replicating DNA. PCNA trimers may bind either three molecules of the same replication factor or different combinations of replication factors.

Figure 2

Dynamics of the DNA synthesome. Chromatin binding of the DNA synthesomes might be regulated by cyclin-dependent protein kinase (Cdk)/cyclin complexes. At the G1/S-phase transition (left side of panel), the DNA synthesomes are maintained in a free or chromatin-unbound state through their association with Cdk2/cyclin A complexes. In S phase (centre, top of panel), two kinds of DNA synthesome exist: the one that is not associated with the chromatin contains both cyclin A and Cdk2, and the one that is chromatin-associated contains cyclin A but not Cdk2. The equilibrium between these two forms is regulated by the association–dissociation dynamics of Cdk2 (as indicated by the black arrows). During the G2 phase (right lower side of panel), Cdk2 is replaced by Cdk1 and both cyclin B and cyclin A associate with the free complex. This prevents further association with chromatin, thus shifting the equilibrium towards the chromatin-unbound state. It is not yet known whether such an inactive complex is targeted for degradation during M phase or is re-used in the subsequent cell cycle.