Figure 7. MCM2–7-mediated cohesin loading and mobilization promote sister-chromatid cohesion.

In this speculative model, SCC2/4 (NIPBL/MAU2 in humans) associates with DDK and the dormant, phosphorylated MCM2–7, and promotes cohesin loading at the G1/S boundary. The loaded cohesin remains physically associated with SCC2/4, DDK, and MCM2–7. Upon the activation of the helicase activity of MCM2–7 and the initiation of DNA replication, cohesin bound to the dormant MCM2–7 is mobilized and held at the active replication forks, through a process that requires SCC2/4, DDK, and a multitude of replisome components, including RPA. Cohesin bound to the replication fork is then deposited behind the fork prior to the completion of lagging strand synthesis and histone deposition, and entraps both sister chromatids to establish sister-chromatid cohesion.

Figure 7––Figure Supplement 1. DDK-bound, potentiated MCM promotes cohesin loading and mobilization.

Based on this model, only the potentiated MCM complexes bound to DDK (which is limiting) can recruit cohesin and SCC2/4 (NIPBL/MAU2 in humans). These potentiated complexes are destined to fire early during DNA replication, thus marking the early-replicating origins. In thymidine-arrested cells, a large fraction of these early-replicating origins has fired. Continued binding of cohesin and SCC2/4 at these origins requires replisome components in these early S phase cells. During S phase progression, DDK is mobilized and binds to other MCM complexes. These potentiated MCM complexes at late-replicating origins then recruit cohesin and SCC2/4 and repeat the process of cohesin loading and mobilization.