Sticking a fork in cohesin - it's not done yet!

To identify the products of chromosome replication (termed sister chromatids) from S-phase through M-phase of the cell cycle, each sister pair becomes tethered together by specialized protein complexes termed cohesins. To participate in sister tethering reactions, chromatin-bound cohesins become modified by establishment factors that function during S-phase and bind to DNA replication-fork components. Early models posited that establishment factors might move with replication forks, but that fork progression takes place independently of cohesion pathways. Recent studies now suggest that progression of the replication fork and/or S-phase are slowed in cohesion-deficient cells. These findings have led to speculations that cohesin ring-like structures normally hinder fork progression but coordinate origin firing during replication. Neither model, however, fully explains the diverse effects of cohesion mutation on replication kinetics. I discuss these challenges and then offer alternative views that include cohesin-independent mechanisms for replication-fork destabilization and transcription-based effects on S-phase progression.