Evidence that replication fork components catalyze establishment of cohesion between sister chromatids

Abstract

Accurate chromosome segregation requires that replicated sister chromatids are held together until anaphase, when their "cohesion" is dissolved, and they are pulled to opposite spindle poles by microtubules. Establishment of new cohesion between sister chromatids in the next cell cycle is coincident with replication fork passage. Emerging evidence suggests that this temporal coupling is not just a coincident timing of independent events, but rather that the establishment of cohesion is likely to involve the active participation of replication-related activities. These include PCNA, a processivity clamp for some DNA polymerases, Trf4/Pol final sigma (formerly Trf4/Pol kappa), a novel and essential DNA polymerase, and a modified Replication Factor C clamp--loader complex. Here we describe recent advances in how cohesion establishment is linked to replication, highlight important unanswered questions in this new field, and describe a "polymerase switch" model for how cohesion establishment is coupled to replication fork progression. Building the bridges between newly synthesized sister chromatids appears to be a fundamental but previously unrecognized function of the eukaryotic replication machinery.

Figure 1

Steps in sister chromatid cohesion during the chromosome cycle. Red lines represent a single double-stranded chromosome, and blue lines represent cohesive bonds between chromatids.

Figure 2

The “Cohesin” complex is a key component of the chromatid glue. (A) SMC heterodimers are shown in an extended conformation, which may allow simultaneous binding of two sister chromatids. (B) SMC heterodimers are shown with the hinge region flexed, so that a pair of heterodimers could be bridged by non-SMC subunits.

Figure 3

Model for cohesion establishment by replication-related activities. Precohesion site is meant to show the cohesin complex, because it is known to bind to G₁ chromosomes. A cohesion site is a functional protein bridge formed after fork passage. The cartoon is not meant to imply the existence of direct protein–protein interactions, because such interactions have not been demonstrated to date.

Figure 4

Polymerase switching on Okazaki fragments may be analogous to what happens at cohesion sites.