Establishment of sister chromatid cohesion

Abstract

The process of sister chromatid pairing, or cohesion establishment, is coupled to DNA replication and fundamental to proper chromosome segregation and cell viability. In the past year, several articles have provided important new insights into cohesion establishment, an activity predicated on the acetyltransferase Ctf7/Eco1. Here, I review new findings that the conversion of chromatid-bound cohesins into a cohesion-competent state involves Ctf7/Eco1-mediated acetylation of the cohesin subunit Smc3. These studies further explore an anti-establishment activity that involves the binding of accessory factors WAPL/Rad61 and Pds5 to the cohesin subunit Scc3/Irr1. The anti-establishment activity of WAPL/Rad61 and Pds5 is temporarily relaxed by Ctf7/Eco1 during S phase to promote sister chromatid pairing. These findings are likely to be of clinical relevance, given the role of cohesion pathways in a wide range of disease states.

Figure 1. Cohesin complex assembly and structure

SMCs contain long helical domains interrupted by a centrally positioned hinge. Hinge folding enables the helical domains to intertwine in an anti-parallel fashion and form a stable coiled-coil rod-like structure. Folding over also brings amino- and carboxy-terminal globular ATPase domains for each SMC into registration. Smc1/3 bind together by dimerization of hinge domains and by association of globular head domains. The Smc1/3 ATPase domains are capped by Mcd1/Scc1. Mcd1/Scc1 recruits Scc3/Irr1.

Figure 2. Chromatid capture

(A) Current models suggest that Smc1/3 subunit interactions are dynamic: either hinge dimerization domains or ATPase globular head domains may transiently let go. DNA is then thought to enter the exposed lumen, becoming trapped upon reformation of Smc1/3 subunit interactions. Other models of cohesin association with chromatin (lateral binding, filamentous or spiraled structures) are not shown. DNA is depicted in a ‘naked’ state — note that a single 30 nm compacted chromatin fiber would completely fill the proposed lumen and distort the coiled-coil domains of the Smc1/3 complex (not shown). (B) Cohesin deposition and chromatid capture may be coupled to DNA replication. Deposition factors Scc2 and Scc4 are not shown; leading and lagging replisome complexes are simplified to a large hexagon.

Figure 3. Cohesion establishment

Shown is a speculative model regarding the conversion of cohesins to a cohesion-competent state during S phase. Cohesin complexes deposited onto (or entrapping) each chromatid are separate and distinct entities. Recruitment of anti-establishment factors Pds5 and WAPL/Rad61 onto Scc3/Irr1 precludes the tethering together of cohesin complexes by destabilizing cohesin–cohesin association. Lines of evidence equally support recruitment of Pds5 to both Scc3/Irr1 and to hinge dimerization domains, suggesting that either cohesin terminus may participate in pairing. Pds5 and WAPL/Rad61 anti-establishment factors may also promote chromatid capture reactions by destabilizing subunit interactions within each cohesin (not shown). During S phase, Ctf7/Eco1 acetylates Smc3 near the ATPase globular domain. Smc3 acetylation temporarily inhibits anti-establishment activity, possibly by altering the association or binding site of WAPL/Rad61 and Pds5 to the rest of the cohesin complex (note rotation of anti-establishment factors shown for instance in model 2). Dimerization of cohesins associated with each sister chromatid results in a stable structure that is resistant to antiestablishment activity and persistent Smc3 acetylation. Two of several oligomeric structures (model 1 and model 2) that account for both DNA entrapment and sister chromatid pairing are shown (see [27,28] for a single ring model). In a G2/M response to DNA damage, chromatin-bound cohesins are instead converted to a pairing state by Mcd1 phosphorylation and subsequent acetylation (not shown).