Sister acts: coordinating DNA replication and cohesion establishment

Abstract

The ring-shaped cohesin complex links sister chromatids and plays crucial roles in homologous recombination and mitotic chromosome segregation. In cycling cells, cohesin's ability to generate cohesive linkages is restricted to S phase and depends on loading and establishment factors that are intimately connected to DNA replication. Here we review how cohesin is regulated by the replication machinery, as well as recent evidence that cohesin itself influences how chromosomes are replicated.

Figure 1.

The Scc2–Scc4 cohesin-loading complex is targeted to chromosomes via both replication-dependent and replication-independent mechanisms. In Xenopus egg extracts, the Scc2–Scc4 complex binds chromatin through specific interactions with pre-RCs via the S-phase kinase Cdc7. In contrast, the yeast Scc2–Scc4 complex associates with chromatin and loads cohesin even when pre-RC assembly is prevented. Whether yeast Scc2–Scc4 binds chromosomes directly or through an alternative targeting factor (denoted here by the question mark) is not known.

Figure 2.

Building cohesion at the replication fork. At S-phase onset, replication forks encounter cohesin rings that are unacetylated and tightly bound to Wapl and Pds5, which antagonize cohesion establishment and replication fork progression. Through recruitment and activation of Eco1-related acetyltransferases, replication forks modify cohesin's Smc3 subunit to weaken its interaction with the Wapl–Pds5 complex. This may put cohesin in an “open” conformation that allows the replication fork to progress while trapping the nascent sister chromatids inside the ring. Alternatively, it is possible that cohesin rings are displaced by advancing replication forks, but then are subjected to a second round of loading behind the fork. However generated, entrapment of the nascent sister DNAs is likely to enhance fork stability by enabling homology-dependent pathways of fork repair and restart. Further discussion of these points can be found in the text.