Skip to main content
PMC home page
EMBO Reports logoLink to EMBO Reports
. 2009 Sep 11;10(10):1095–1102. doi: 10.1038/embor.2009.207

A matter of choice: the establishment of sister chromatid cohesion

Frank Uhlmann 1
PMCID: PMC2744122  PMID: 19745840

Abstract

Sister chromatid cohesion is the basis for the recognition of chromosomal DNA replication products for their bipolar segregation in mitosis. Fundamental to sister chromatid cohesion is the ring-shaped cohesin complex, which is loaded onto chromosomes long before the initiation of DNA replication and is thought to hold replicated sister chromatids together by topological embrace. What happens to cohesin when the replication fork approaches, and how cohesin recognizes newly synthesized sister chromatids, is poorly understood. The characterization of a number of cohesion establishment factors has begun to provide hints as to the reactions involved. Cohesin is a member of the evolutionarily conserved family of Smc subunit-based protein complexes that contribute to many aspects of chromosome biology by mediating long-range DNA interactions. I propose that the establishment of cohesion equates to the selective stabilization of those cohesin-mediated DNA interactions that link sister chromatids in the wake of replication forks.

Keywords: DNA replication, sister chromatid cohesion, chromosome segregation, cohesin, Smc complexes

See Glossary for abbreviations used in this article

Glossary.

Chl

chromosome loss

chromosome segregation in meiosis

CCCTC-binding factor

chromosome transmission fidelity

defective in sister chromatid cohesion

establishment of cohesion

essential for S-chromatin organization

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Csm

chromosome segregation in meiosis

CCCTC-binding factor

chromosome transmission fidelity

defective in sister chromatid cohesion

establishment of cohesion

essential for S-chromatin organization

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

CTCF

CCCTC-binding factor

chromosome transmission fidelity

defective in sister chromatid cohesion

establishment of cohesion

essential for S-chromatin organization

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Ctf

chromosome transmission fidelity

defective in sister chromatid cohesion

establishment of cohesion

essential for S-chromatin organization

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Dcc

defective in sister chromatid cohesion

establishment of cohesion

essential for S-chromatin organization

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Eco

establishment of cohesion

essential for S-chromatin organization

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Eso

essential for S-chromatin organization

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Fen

flap endonuclease

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

MCM

minichromosome maintenance

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Mrc

mediator of the replication checkpoint

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

PCNA

proliferating cell nuclear antigen

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Pds

precocious dissociation of sister chromatids

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

RFC

replication factor C

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Scc

sister chromatid cohesion

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Smc

structural maintenance of chromosomes

topoisomerase-1-associated factor

transfer RNA

wings apart-like

Tof

topoisomerase-1-associated factor

transfer RNA

wings apart-like

tRNA

transfer RNA

wings apart-like

Wapl

wings apart-like

Introduction

Eukaryotic cells inherit much of their genomes in the form of chromosomes during cell division. After DNA replication occurs in S-phase, sister chromatids remain tightly linked in pairs by the cohesin complex. This facilitates their tension-generating bi-orientation on the mitotic spindle, before a protease known as separase cleaves the cohesin complex to liberate sister chromatids for movement towards the spindle poles.

Cohesin is a multisubunit protein complex, shaped like a large proteinaceous ring, which is loaded onto chromosomes—during telophase in human cells and in late G1-phase in budding yeast—by the Scc2/4 cohesin loading complex. During DNA replication in S-phase, when the cohesion between sister chromatids is established, cohesin topologically embraces and entraps replication products (Haering et al, 2008). Sister chromatid cohesion forms the basis not only of chromosome segregation, but also of DNA break repair by homologous recombination during the G2-phase of the cell cycle. In addition, cohesin mediates chromosome condensation and long-range DNA interactions that are part of transcriptional insulators and boundary elements, independently of sister chromatid cohesion. Recent reviews have surveyed the molecular biology of cohesin (Losada & Hirano, 2005; Nasmyth & Haering, 2005; Onn et al, 2008). Here, I discuss how cohesin establishes specific and enduring linkages between sister chromatids, by drawing on a comparison with related Smc complexes and their ability to promote DNA interactions.

The ancestors of cohesin

Cohesin is a member of an evolutionarily conserved family of Smc subunit-based protein complexes, which are characterized by a dimer of long flexible Smc subunits that give the complexes their ring shape through head-to-head and tail-to-tail interactions (Anderson et al, 2002; Haering et al, 2002; Melby et al, 1998). The heads of the Smc complexes consist of ATPase domains, the activity of which is essential for their function. In the case of cohesin, mutations in the ATPase prevent it from loading onto chromosomes, suggesting that the ATPase activity mediates an opening reaction through which DNA enters the cohesin ring (Arumugam et al, 2003; Weitzer et al, 2003). All Smc complexes contain several additional essential subunits. Of note is the conserved kleisin subunit, which binds to the Smc heads directly and stabilizes their interaction (Haering et al, 2002); the cleavage of the kleisin Scc1 by separase destroys the cohesin ring in anaphase (Uhlmann et al, 2000). Given their striking similarities, and in the absence of evidence to the contrary, we can assume that all Smc complexes act by topologically entrapping more than one strand of DNA in an ATP hydrolysis-dependent reaction.

Prokaryotic Smc complexes compact the bacterial chromosome and promote its resolution and segregation to daughter cells after DNA replication. They may achieve this by establishing long-range DNA interactions between two different Smc binding sites, which are found at places of strong transcription along the chromosome arms and are enriched around cis-acting partitioning sequences (Gruber & Errington, 2009; Fig 1A). This ancestral function of Smc complexes is largely recapitulated in eukaryotes by the condensin complex; like its prokaryotic counterpart, condensin promotes the compaction of chromosomes and sister chromatid resolution. The binding pattern of the complexes is strikingly conserved between bacteria and eukaryotes, with enrichment at strongly transcribed regions along chromosome arms and around centromeres, which form the eukaryotic partitioning locus (D'Ambrosio et al, 2008b; Jans et al, 2009). As in prokaryotes, the mechanism by which condensin compacts chromosomes is still unclear. It is tempting to speculate that condensin promotes interactions between two or more of its binding sites, perhaps by the sequential topological capture of distinct DNA sequences as they come into spatial proximity by Brownian motion (Fig 1B). A proof of principle is provided by the observation of condensin-dependent clustering of tRNA gene loci—a prominent class of condensin binding sites—in the budding yeast nucleus (Haeusler et al, 2008). Whether the interactions between condensin binding sites follow an underlying organizing principle, or are largely self-organizing according to proximity along the primary DNA sequence, is not known. The function of condensin in sister chromatid resolution, which is probably to facilitate the decatenation of topological DNA links that persist after the termination of DNA replication, is also poorly understood (Bhat et al, 1996; D'Ambrosio et al, 2008a).

Figure 1.

Figure 1

Open in a new tab

Comparison of Smc complexes and their possible modes of action on chromosomes. (A) Cartoon of the subunit composition of the bacterial Smc complex, its binding sites along the circular bacterial chromosome, and a proposal of how it might compact the chromosome by establishing links between neighbouring binding sites. The movement of bacterial replication products towards opposite cell poles initiates from the parS partitioning locus, which is enriched in Smc complexes. Additional binding sites along the chromosome arms correlate with highly expressed genes, such as rRNA (rrn) and tRNA (trn). (B) The eukaryotic condensin complex has a chromosomal association pattern reminiscent of the bacterial Smc complex. It is enriched at the centromere (CEN) and at highly transcribed loci along the chromosome arms, including rRNA, tRNA and ribosomal protein genes (RPS and RPL). Condensin may similarly promote chromosome compaction by establishing interactions between neighbouring binding sites. The enrichment around the centromere provides additional mechanical stability around this locus during chromosome segregation. (C) Cohesin associates with chromosomes at the same loci as condensin, but shows pronounced translocation on loading in response to transcription, perhaps because of its longer mean residence time on chromosomes. Cohesin also establishes interactions between neighbouring binding sites as part of transcriptional insulators but has specialized in establishing stable interactions between sister chromatids during DNA replication. Brn, barren; Pds, precocious dissociation of sister chromatids; rRNA, ribosmal RNA; Scc, sister chromatid cohesion; Scp, segregation and condensation protein; Smc, structural maintenance of chromosomes; tRNA, transfer RNA; Wapl, wings apart-like; Ycg, yeast CapG; Ycs, yeast condensin subunit.

What is so special about cohesin?

The similarities between cohesin and condensin are worth noting. In both budding and fission yeast, cohesin and condensin load onto chromosomes at the same sites (D'Ambrosio et al, 2008b; Lengronne et al, 2004; Schmidt et al, 2009). The loading of cohesin at these sites depends on the Scc2/4 cohesin loading complex, the mechanism of action of which is still unclear (Ciosk et al, 2000). Scc2/4 might be the major determinant of these loading sites, to which—at least in budding yeast—Scc2/4 also recruits condensin and a third Smc complex, Smc5/6 (Betts Lindroos et al, 2006). This has not yet been seen in other organisms in which condensin might alternatively—or additionally—be able to recognize its loading sites independently of Scc2/4.

A distinguishing feature of cohesin is that, on loading, the complex translocates along the DNA in a manner consistent with downstream movement along RNA polymerase II-transcribed genes (Lengronne et al, 2004; Schmidt et al, 2009). This translocation is most prominently observed in budding and fission yeast, although not all cohesin translocates in the latter. In Drosophila, cohesin largely remains close to its loading complex (Misulovin et al, 2008). Although the significance of the translocation reaction remains unknown, it might hint at a specific feature of cohesin. Translocation in response to transcription might reflect the long average time that cohesin resides on chromatin, which allows it to hold topologically onto chromosomes while the transcription machinery travels along the relatively short yeast genes. Several measurements of the stability of cohesin on chromosomes (Bernard et al, 2008; Gerlich et al, 2006b; Kueng et al, 2006; McNairn & Gerton, 2009; Rowland et al, 2009) suggest an average residence time in the range of minutes, a long time for any molecular interaction. Evidence for translocation has also been obtained for condensin, but the greater dissociation rate of this complex, at least in interphase, might largely obscure this process (D'Ambrosio et al, 2008b; Gerlich et al, 2006a; Johzuka & Horiuchi, 2007).

Although cohesin has a longer average residence time than condensin, the two complexes could in principle perform a similar reaction, namely the subsequent topological entrapment of more than one strand of DNA (Fig 1C). This has been suggested by recent studies of the contribution of mammalian cohesin to transcriptional regulation, which show that cohesin mediates long-range interactions between neighbouring binding sites that also bind to the CTCF transcriptional insulator (Hadjur et al, 2009; Mishiro et al, 2009). According to this finding, cohesin—similarly to all Smc complexes—acts by establishing interactions between distant binding sites. The specificities of the Smc complexes for particular interaction sites could be afforded in part by their unique subunit composition.

Cohesin acetylation and stability on chromosomes

On the basis of these considerations, how does cohesin promote sister chromatid cohesion? I propose that two aspects of cohesin have singled it out to become the crucial mediator of sister chromatid cohesion: its mechanism of targeting to regions where newly replicated sister chromatids interact, and the stabilization of the cohesin-mediated interactions linking DNA replication products.

Once loaded onto chromosomes, cohesin has a slow off-rate that is in the region of minutes. Is this sufficient for promoting enduring sister chromatid cohesion? As chromosomes come under tension from the mitotic spindle, a directional pull is exerted towards separating sister chromatids. Even with a residence time of minutes, sister chromatids would separate slowly but progressively. To prevent this, an even more stable interaction of cohesin with chromosomes is required. Indeed, there is good evidence that at least a subpool of cohesin becomes significantly stabilized on chromosomes after DNA replication. The direct observation of cohesin dynamics on mammalian chromosomes revealed that during the course of S-phase, approximately one-third of all cohesin becomes stably linked to chromosomes, with a mean residence time of at least 6 hours (Gerlich et al, 2006b). In addition, evidence from budding yeast suggests that after DNA replication there is no measurable exchange of the functional pool of cohesin that mediates sister chromatid cohesion (Haering et al, 2004). In fission yeast, cohesin dissociates from chromosomes if its loading complex is inactivated in the G1-phase, but not after DNA replication in the G2-phase of the cell cycle (Bernard et al, 2008).

One hint as to how this nearly permanent stabilization of cohesin is achieved comes from studies of two regulators of the complex. The first is a protein known as Wapl, which binds to cohesin and promotes its dissociation from chromosomes. In the absence of Wapl, cohesin associates more stably with both human and fission yeast chromosomes. In human cells, Wapl promotes the dissociation of a substantial pool of cohesin from chromosomes during prophase (Bernard et al, 2008; Gandhi et al, 2006; Kueng et al, 2006).

The second regulator is the acetyltransferase Eco1, which early studies have identified as a cohesion establishment factor, a protein that is required for the generation of stable sister chromatid cohesion but is not part of the cohesin complex (Ivanov et al, 2002; Skibbens et al, 1999; Tóth et al, 1999). In fission yeast, the Eco1 orthologue Eso1 is required for the stabilization of cohesin as cells progress through S-phase (Bernard et al, 2008). The mechanism of action of Eco1 has since been unveiled: it associates with the DNA replication fork, probably through an interaction with the multifunctional DNA polymerase processivity factor PCNA (Lengronne et al, 2006; Moldovan et al, 2006), and acetylates the cohesin subunit Smc3 during DNA replication when the fork passes cohesin binding sites (Ben-Shahar et al, 2008; Ünal et al, 2008; Zhang et al, 2008). Smc3 acetylation explains the essential function of Eco1 in the establishment of cohesion, as indicated by the analysis of non-acetylatable and acetylation-mimicking mutations of two conserved Smc3 acetylation sites. However, it is not only acetylation-mimicking mutations in Smc3 that make Eco1 dispensable for sister chromatid cohesion; the deletion of Wapl from budding yeast cells has the same effect (Ben-Shahar et al, 2008; Rowland et al, 2009; Sutani et al, 2009), suggesting that Smc3 acetylation counteracts Wapl. Considering the role of Wapl in promoting cohesin dissociation from chromosomes, one simple hypothesis is that the role of Smc3 acetylation in the establishment of cohesion is to generate a stable Wapl-resistant cohesin pool (Fig 2A). In addition to acetylation-mimicking mutations in Smc3, a number of other point mutations in Smc3 and the cohesin subunits Scc3 and Pds5 allow for the establishment of cohesion in the absence of Eco1 (Rowland et al, 2009; Sutani et al, 2009). These mutations could demarcate surfaces of interaction that mediate the destabilization of cohesin by Wapl. This hypothesis does not exclude the fact that Smc3 acetylation could have other consequences for the cohesin complex that facilitate the establishment of cohesion (Ben-Shahar et al, 2008; Rowland et al, 2009).

Figure 2.

Figure 2

Open in a new tab

Establishment of sister chromatid cohesion. (A) Establishment of cohesion during DNA replication. Replication fork-associated Eco1 acetylates Smc3, which renders cohesin resistant to the destabilizing activity of Wapl, a prerequisite for enduring sister chromatid cohesion. How Wapl destabilizes cohesin, and what further impact it has on the establishment of cohesion, is not known. Several additional cohesion establishment factors are depicted at the replication fork. Their mechanism of action is unknown, but they could aid the passage of the replication fork through cohesin rings, potentially by coordinating lagging strand loop release with the encounter of cohesin. (B) Cohesion establishment in response to DNA breaks in G2. The ability of cohesin to link two of its binding sites might establish interactions between sister chromatids because of their proximity in G2. In response to DNA damage, Eco1 stabilizes these links by Scc1 acetylation, which might be aided by the recruitment of Eco1 to break sites and genome-wide Scc1 phosphorylation by the damage-activated Chk1 kinase. Ac, acetyl group; Chl, chromosome loss; Csm, chromosome segregation in meiosis; Ctf, chromosome transmission fidelity; Eco, establishment of cohesion; Fen, flap endonuclease; Mrc, mediator of the replication checkpoint; PCNA, proliferating cell nuclear antigen; RFC, replication factor C; Scc, sister chromatid cohesion; Smc, structural maintenance of chromosomes; Tof, topoisomerase-1-associated factor; Wapl, wings apart-like.

In the absence of Eco1 and Wapl, sister chromatid cohesion is functional, albeit compromised. There is no pronounced cohesin removal in prophase during budding yeast mitosis, and whether the main function of Wapl is to add robustness to the establishment of cohesion or is unrelated to sister chromatid cohesion remains to be clarified. An additional regulator of cohesin stability in human cells, Sororin, has not yet been identified in yeast (Rankin et al, 2005; Schmitz et al, 2007). Whether Sororin impacts on Smc3 acetylation and acts as a cohesion establishment factor, or whether it has an independent role in maintaining cohesin stability after DNA replication, will be interesting to address.

How does cohesin choose sister chromatids?

One could imagine that the mere proximity of DNA replication products, as they emerge from the replication fork, gives cohesin—or any other Smc complex (Lam et al, 2006)—a high likelihood of establishing interactions between them by sequential topological embrace. Given the localization of Eco1 at the replication fork, the cohesin rings that link replication products have a good chance to become acetylated and thus stabilized. In principle, this mechanism might suffice to establish stable sister chromatid cohesion, and there is no reason to believe that it does not take place. However, there is evidence that this is not the only, and maybe not the main, mechanism by which sister chromatids are linked.

The possibility that contacts between two sister chromatids are established when they are in close proximity, immediately after their synthesis, requires that cohesin is loaded onto at least one of the two newly synthesized replication products after the replication fork has passed. This would require the renewed action of the cohesin loading complex Scc2/4 and renewed ATP hydrolysis. By contrast, Scc2/4 and a motif in the cohesin ATPase that is required for swift loading of cohesin onto DNA before S-phase are not strictly required for the establishment of sister chromatid cohesion (Lengronne et al, 2006). This of course does not exclude the possibility that an as yet uncharacterized alternative cohesin loading reaction takes place close to replication forks. However, an attractive alternative would be that no new DNA contacts need to be made during the establishment of cohesion and that the two replication products are left within the cohesin ring after the replisome passes through its centre (Haering et al, 2002).

Additional establishment factors at the fork

In addition to Eco1, several non-essential cohesion establishment factors have been identified in budding yeast, many of which are known to be linked to the replication fork machinery (Hanna et al, 2001; Mayer et al, 2001, 2004; Petronczki et al, 2004; Skibbens, 2004; Warren et al, 2004). These factors have been divided by genetic epistasis analysis into two groups (Xu et al, 2007); the components of either group can be deleted without loss of cell viability, but the simultaneous inactivation of factors in both groups is lethal. Both epistasis groups are required for the establishment of sister chromatid cohesion during S phase, but not for the maintenance of cohesion once it is established (Xu et al, 2007). What can we learn from these factors about the cohesion establishment process?

The first group includes the Ctf18, Ctf8 and Dcc1 subunits of an alternative RFC complex (RFCCtf18), which is able to load PCNA onto DNA (Bermudez et al, 2003; Mayer et al, 2001). The absence of RFCCtf18 leads to reduced PCNA levels in the vicinity of replication forks (Lengronne et al, 2006). Cohesion defects have also been seen after the mutation of RFC core subunits and PCNA itself, and genetic interactions between PCNA and Eco1 have been documented (Moldovan et al, 2006; Skibbens et al, 1999). If PCNA recruits Eco1 to replication forks, RFCCtf18 could act upstream from Eco1. However, other explanations cannot be excluded, as PCNA is the landing platform for a large number of enzymatic activities at replication forks that are involved in processes such as lesion bypass, Okazaki fragment maturation and chromatin assembly. The RFCCtf18 epistasis group also contains the replication checkpoint mediator protein Mrc1, the presence of which at the fork—but not its checkpoint activity—contributes to the establishment of cohesion in an unknown manner (Katou et al, 2003; Xu et al, 2004).

The second epistasis group is assembled around Ctf4, a central component of the replisome progression complex that mediates protein interactions between the MCM DNA helicase and the DNA polymerase α/primase complex at the replication fork (Gambus et al, 2006; Hanna et al, 2001; Tanaka et al, 2009; Zhu et al, 2007). This group also contains the Ctf4-interacting replication pausing regulators Tof1 and Csm3, the role of which during undisturbed S-phase progression is unclear. These proteins could act in a second pathway to recruit Eco1 to replication forks independently of PCNA. Alternatively, the Ctf4-dependent link of DNA helicase and primase could regulate the initiation of Okazaki fragment synthesis during lagging strand replication, as occurs in prokaryotic replication systems (Tougu & Marians, 1996). An implication of lagging strand reactions in the establishment of cohesion comes from another establishment factor in this epistasis group, the Chl1 helicase (Farina et al, 2008; Gerring et al, 1990; Petronczki et al, 2004; Skibbens, 2004), which stimulates the Fen1 flap endonuclease, a key enzyme during Okazaki fragment processing. Notably, mutation or depletion of Fen1 also causes a sister chromatid cohesion defect (Farina et al, 2008; Yuen et al, 2007).

How do these contributors relate to cohesion establishment? No stable interactions between any of these factors and cohesin—which could have indicated their participation in a potential cohesin opening reaction as part of cohesion establishment—have been documented. Could the replication fork traverse through cohesin rings to leave replication products trapped inside? If this were the case, the geometry of the replisome would probably be crucial to its success in passing through cohesin without disrupting the ring. A model of a eukaryotic replication fork, based on knowledge of prokaryotic DNA replication, suggests that fork passage might be possible (Lengronne et al, 2006). However, our understanding of the actual arrangement of eukaryotic fork components and the stability of their interactions within the replisome is still incomplete. If the trombone model for Okazaki fragment synthesis holds true for eukaryotes, a potential obstacle to the passage of replication forks through cohesin rings could be the lagging strand loop (Hamdan et al, 2009; Fig 2A). A potential role of the Ctf4 epistasis group could thus be to coordinate fork passage through cohesin rings with Okazaki fragment synthesis, so that loops would be released at the time of cohesin passage. Whether an interaction between cohesin and the MCM helicase is relevant in this process remains to be clarified (Ryu et al, 2006). This is clearly only one possible way in which these diverse replication proteins could impact on the replication fork to facilitate the establishment of cohesion. We also have to consider why cohesin translocates along chromosomes in response to transcription, but not in response to a passing replication fork (Lengronne et al, 2006).

The establishment of cohesion in G2

Sister chromatid cohesion must be established during DNA replication. Once replication is complete, cohesin can still be loaded onto chromosomes but will no longer be able to establish sister chromatid cohesion (Uhlmann & Nasmyth, 1998). There are probably two reasons for this. First, if sister chromatids are not held together when synthesized, they will be free to diffuse away from each other. Once separate, there is no known mechanism that can bring sister chromatids back together. Even homology-based mechanisms that recognize sister chromatids during mitotic repair by homologous recombination appear to depend on, rather than to generate, sister chromatid cohesion (Sjögren & Nasmyth, 2001). Second, even if sister chromatids are correctly paired, cohesin added in the G2-phase of the cell cycle is unable to generate stable cohesive links (Haering et al, 2004; Lengronne et al, 2006). The reason for this becomes apparent from a notable exception.

In response to a double-stranded DNA break in G2, cohesin is recruited to the break site and reinforces sister chromatid cohesion in an Eco1-dependent manner, which is a prerequisite for efficient break repair by homologous recombination (Ström et al, 2004, 2007; Ünal et al, 2007). RFCCtf18 is recruited to the break site and could facilitate the establishment of cohesion by engaging PCNA along with Eco1 (Ogiwara et al, 2007). Notably, cohesin is now enabled to establish sister chromatid cohesion all along the genome, not just around the break site. The overexpression of Eco1 in G2 cells has the same effect, allowing cohesin to establish new genome-wide sister chromatid cohesion.

A possible explanation for these findings is related to the generic ability of cohesin to link two distant binding sites, perhaps by sequential embrace (Hadjur et al, 2009; Mishiro et al, 2009). If sister chromatid cohesion pre-exists, cohesin will have a good chance of linking sister chromatids. This, however, will not provide additional sister chromatid cohesion unless Eco1 stabilizes these links (Fig 2B), which might be achieved by recruiting Eco1 to break sites. In addition, it has been suggested that the checkpoint kinase Chk1 phosphorylates the cohesin subunit Scc1 in response to DNA damage, thereby promoting Scc1 acetylation by Eco1 (Heidinger-Pauli et al, 2008, 2009). Although the capture of sister chromatids might have occurred through different means, the acetylation of Scc1 seems to counteract Wapl, as does replication fork-dependent Smc3 acetylation. The genome-wide reinforcement of sister chromatid cohesion that is achieved in this manner warrants an accurate chromosome segregation as cells exit from the checkpoint arrest (Ünal et al, 2007). At the break site itself, additional sister chromatid cohesion could facilitate recombination reactions and cohesin could alternatively, or additionally, promote interactions between the two sides of the broken DNA strand.

A second exception in which cohesion is established after the completion of DNA replication is evident during the elastic centromere breathing that accompanies the bi-orientation of sister chromatid pairs on the mitotic spindle. Sister sequences transiently split during this process, which is accompanied by a loss of cohesin from centromeres (Eckert et al, 2007; Ocampo-Hafalla et al, 2007). Cohesin is reloaded again when centromeres reassociate, a process which is probably facilitated by a prominent cohesin loading site that exists in the centromere (Lengronne et al, 2004). Notably, Eco1 is required for efficient centromere re-association, suggesting that the re-establishment of cohesion is part of the mechanism that rejoins sister centromeres. The cohesin acetylation site that is targeted in this context remains to be identified. These findings suggest that although initial sister chromatid cohesion must be established during DNA replication, its subsequent modulation is an integral part of the response to DNA damage and to the elastic counterforce of sister centromeres to the mitotic spindle.

Conclusions

Cohesin is one of at least three essential Smc complexes in eukaryotes. Based on their structural resemblance and the emerging similarities in how they load onto chromosomes, it is not surprising that Smc complexes have overlapping roles in the processes of sister chromatid cohesion, chromosome condensation, transcriptional regulation and DNA repair. The crucial step in all of these processes could be the linkage of distant DNA binding sites by topological embrace. However, individual complexes might have additional roles, such as engaging in specific protein interactions or recruiting additional enzymatic activities (Andrews et al, 2005; Chang et al, 2005; Nonaka et al, 2002). An important specialization of the cohesin complex is its marked stabilization on chromosomes, which is a prerequisite to mediate enduring sister chromatid cohesion, and correlates with its acetylation. A second unique feature might lie in its open ring structure, compared to the more pin-like appearance of condensin (Anderson et al, 2002). This could facilitate the passage of the replication fork through cohesin rings as an efficient means to trap replication products, in addition to the generic ability of cohesin to mediate DNA contacts by sequential loading onto more than one binding site. Molecular genetics approaches will continue to increase our understanding of the many roles of Smc complexes in chromosome biology. Ultimately, their molecular mechanism will only be elucidated by using biochemical assays to study their loading onto DNA and by observing their behaviour during the passage of a replication fork. (See Sidebar A)

Sidebar A | In need of answers.

  1. How do Smc complexes link distant strands of DNA? Evidence has shown that single cohesin rings link replicated circular minichromosomes. Is this the universal mechanism, as assumed here, by which all Smc complexes mediate DNA interactions? Two DNA strands could be subsequently embraced by the same Smc complex, but alternative models in which interactions of more than one Smc complex with each other underlie these long-range interactions have been proposed.

  2. What happens to cohesin as the replisome passes? Many aspects of the model in which Eco1-dependent cohesin acetylation by the passing replication fork stabilizes sister chromatid cohesion remain to be tested. Does acetylation change additional features of cohesin that contribute to the establishment of cohesion? What is the precise molecular impact of Wapl on cohesin?

  3. How does cohesin choose sister chromatids? Does the replisome indeed traverse through the cohesin ring? A firm answer to these questions will have to await the reconstitution of cohesin loading onto DNA in vitro, followed by replication using an established in vitro replication system.

graphic file with name embor2009207-i2.jpg

Open in a new tab

Frank Uhlmann

Acknowledgments

I thank the past and present members of my laboratory and many colleagues in the field for stimulating discussions. I apologize for the omission of many important contributions to the field, and their references, owing to space constraints.

References

  1. Anderson DE, Losada A, Erickson HP, Hirano T (2002) Condensin and cohesin display different arm conformations with characteristic hinge angles. J Cell Biol 156: 419–424 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrews EA, Palacek J, Sergeant J, Taylor E, Lehmann AR, Watts FZ (2005) Nse2, a component of the Smc5–6 complex, is a SUMO ligase required for the response to DNA damage. Mol Cell Biol 25: 185–196 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arumugam P, Gruber S, Tanaka K, Haering CH, Mechtler K, Nasmyth K (2003) ATP hydrolysis is required for cohesin's association with chromosomes. Curr Biol 13: 1941–1953 [DOI] [PubMed] [Google Scholar]
  4. Ben-Shahar TR, Heeger S, Lehane C, East P, Flynn H, Skehel M, Uhlmann F (2008) Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion. Science 321: 563–566 [DOI] [PubMed] [Google Scholar]
  5. Bermudez VP, Maniwa Y, Tappin I, Ozato K, Yokomori K, Hurwitz J (2003) The alternative Ctf18-Dcc1-Ctf8-replication factor C complex required for sister chromatid cohesion loads proliferating cell nuclear antigen onto DNA. Proc Natl Acad Sci USA 100: 10237–10242 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bernard P, Schmidt CK, Vaur S, Dheur S, Drogat J, Genier S, Ekwall K, Uhlmann F, Javerzat JF (2008) Cell-cycle regulation of cohesin stability along fission yeast chromosomes. EMBO J 27: 111–121 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Betts Lindroos H, Ström L, Itoh T, Katou Y, Shirahige K, Sjögren C (2006) Chromosomal association of the Smc5/6 complex reveals that it functions in differently regulated pathways. Mol Cell 22: 755–767 [DOI] [PubMed] [Google Scholar]
  8. Bhat MA, Philp AV, Glover DM, Bellen HJ (1996) Chromatid segregation at anaphase requires the barren product, a novel chromosome-associated protein that interacts with topoisomerase II. Cell 87: 1103–1114 [DOI] [PubMed] [Google Scholar]
  9. Chang C-R, Wu C-S, Hom Y, Gartenberg MR (2005) Targeting of cohesin by transcriptionally silent chromatin. Genes Dev 19: 3031–3042 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (2000) Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. Mol Cell 5: 1–20 [DOI] [PubMed] [Google Scholar]
  11. D'Ambrosio C, Kelly G, Shirahige K, Uhlmann F (2008) Condensin-dependent rDNA decatenation introduces a temporal pattern to chromosome segregation. Curr Biol 18: 1084–1089 [DOI] [PubMed] [Google Scholar]
  12. D'Ambrosio C, Schmidt CK, Katou Y, Kelly G, Itoh T, Shirahige K, Uhlmann F (2008) Identification of cis-acting sites for condensin loading onto budding yeast chromosomes Genes Dev 22: 2215–2227 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Eckert CA, Gravdahl DJ, Megee PC (2007) The enhancement of pericentromeric cohesin association by conserved kinetochore components promotes high-fidelity chromosome segregation and is sensitive to microtubule-based tension. Genes Dev 21: 278–291 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Farina A, Shin J-H, Kim D-H, Bermudez VP, Kelman Z, Seo Y-S, Hurwitz J (2008) Studies with the human cohesion establishment factor, ChlR1. J Biol Chem 283: 20925–20936 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gambus A, Jones RC, Sanchez-Diaz A, Kanemaki M, van Deursen F, Edmondson RD, Labib K (2006) GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol 8: 358–366 [DOI] [PubMed] [Google Scholar]
  16. Gandhi G, Gillespie PJ, Hirano T (2006) Human Wapl is a cohesin-binding protein that promotes sister-chromatid resolution in mitotic prophase. Curr Biol 16: 2406–2417 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gerlich D, Hirota T, Koch B, Peters J-M, Ellenberg J (2006) Condensin I stabilizes chromosomes mechanically through a dynamic interaction in live cells. Curr Biol 16: 333–344 [DOI] [PubMed] [Google Scholar]
  18. Gerlich D, Koch B, Dupeux F, Peters J-M, Ellenberg J (2006) Live-cell imaging reveals a stable cohesin-chromatin interaction after but not before DNA replication. Curr Biol 16: 1571–1578 [DOI] [PubMed] [Google Scholar]
  19. Gerring SL, Spencer F, Hieter P (1990) The CHL1(CTF1) gene product of Saccharomyces cerevisiae is important for chromosome transmission and normal cell cycle progression in G2/M. EMBO J 9: 4347–4358 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gruber S, Errington J (2009) Recruitment of condensin to replication origin regions by ParB/SpoOJ promotes chromosome segregation in B subtilis. Cell 137: 685–696 [DOI] [PubMed] [Google Scholar]
  21. Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, Fisher AG, Merkenschlager M (2009) Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460: 410–413 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Haering CH, Farcas AM, Arumugam P, Metson J, Nasmyth K (2008) The cohesin ring concatenates sister DNA molecules. Nature 454: 297–301 [DOI] [PubMed] [Google Scholar]
  23. Haering CH, Löwe J, Hochwagen A, Nasmyth K (2002) Molecular architecture of SMC proteins and the yeast cohesin complex. Mol Cell 9: 773–788 [DOI] [PubMed] [Google Scholar]
  24. Haering CH, Schoffnegger D, Nishino T, Helmhart W, Nasmyth K, Löwe J (2004) Structure and stability of cohesin's Smc1-kleisin interaction. Mol Cell 15: 951–964 [DOI] [PubMed] [Google Scholar]
  25. Haeusler RA, Pratt-Hyatt M, Good PD, Gipson TA, Engelke DR (2008) Clustering of yeast tRNA genes is mediated by specific association of condensin with tRNA gene transcription complexes. Genes Dev 22: 2204–2214 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hamdan SM, Loparo JJ, Takahashi M, Richardson CC, van Oijen AM (2009) Dynamics of DNA replication loops reveal temporal control of lagging-strand synthesis. Nature 457: 336–339 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hanna JS, Kroll ES, Lundblad V, Spencer FA (2001) Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion. Mol Cell Biol 21: 3144–3158 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Heidinger-Pauli JM, Ünal E, Guacci V, Koshland D (2008) The kleisin subunit of cohesin dictates damage-induced cohesion. Mol Cell 31: 47–56 [DOI] [PubMed] [Google Scholar]
  29. Heidinger-Pauli JM, Ünal E, Koshland D (2009) Distinct targets of the Eco1 acetyltransferase modulate cohesion in S phase and in response to DNA damage. Mol Cell 34: 311–321 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ivanov D, Schleiffer A, Eisenhaber F, Mechtler K, Haering CH, Nasmyth K (2002) Eco1 is a novel acetlytransferase that can acetylate proteins involved in cohesion. Curr Biol 12: 323–328 [DOI] [PubMed] [Google Scholar]
  31. Jans J, Gladden JM, Ralston EJ, Pickle CS, Michel AH, Pferdehirt RR, Eisen MB, Meyer BJ (2009) A condensin-like dosage compensation complex acts at a distance to control expression throughout the genome. Genes Dev 23: 602–618 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Johzuka K, Horiuchi T (2007) RNA polymerase I transcription obstructs condensin association with 35S rRNA coding regions and can cause contraction of long repeat in Saccharomyces cerevisiae. Genes Cells 12: 759–771 [DOI] [PubMed] [Google Scholar]
  33. Katou Y, Kanoh Y, Bandoh M, Noguchi H, Tanaka H, Ashikari T, Sugimoto K, Shirahige K (2003) S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424: 1078–1083 [DOI] [PubMed] [Google Scholar]
  34. Kueng S, Hegemann B, Peters BH, Lipp JJ, Schleiffer A, Mechtler K, Peters J-M (2006) Wapl controls the dynamic association of cohesin with chromatin. Cell 127: 955–967 [DOI] [PubMed] [Google Scholar]
  35. Lam WW, Peterson EA, Yeung M, Lavoie BD (2006) Condensin is required for chromosome arm cohesion during mitosis. Genes Dev 20: 2973–2984 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lengronne A, Katou Y, Mori S, Yokobayashi S, Kelly GP, Itoh T, Watanabe Y, Shirahige K, Uhlmann F (2004) Cohesin relocation from sites of chromosomal loading to places of convergent transcription. Nature 430: 573–578 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Lengronne A, McIntyre J, Katou Y, Kanoh Y, Hopfner K-P, Shirahige K, Uhlmann F (2006) Establishment of sister chromatid cohesion at the S cerevisiae replication fork. Mol Cell 23: 787–799 [DOI] [PubMed] [Google Scholar]
  38. Losada A, Hirano T (2005) Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev 19: 1269–1287 [DOI] [PubMed] [Google Scholar]
  39. Mayer ML, Gygi SP, Aebersold R, Hieter P (2001) Identification of RFC(Ctf18p, Ctf8p, Dcc1p): an alternative RFC complex required for sister chromatid cohesion in S cerevisiae. Mol Cell 7: 959–970 [DOI] [PubMed] [Google Scholar]
  40. Mayer ML et al. (2004) Identification of protein complexes required for efficient sister chromatid cohesion. Mol Biol Cell 15: 1736–1745 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. McNairn AJ, Gerton JL (2009) Intersection of ChIP and FLIP, genomic methods to study the dynamics of the cohesin proteins. Chromosome Res 17: 155–163 [DOI] [PubMed] [Google Scholar]
  42. Melby TE, Ciampaglio CN, Briscoe G, Erickson HP (1998) The symmetrical structure of structural maintenance of chromosomes (SMC) and MukB proteins: long, antiparallel coiled coils, folded at a flexible hinge. J Cell Biol 142: 1595–1604 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Mishiro T, Ishihara K, Hino S, Tsutsumi S, Aburatani H, Shirahige K, Kinoshita Y, Nakao M (2009) Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster. EMBO J 28: 1234–1245 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Misulovin Z et al. (2008) Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome. Chromosoma 117: 89–102 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Moldovan G-L, Pfander B, Jentsch S (2006) PCNA controls establishment of sister chromatid cohesion during S phase. Mol Cell 23: 723–732 [DOI] [PubMed] [Google Scholar]
  46. Nasmyth K, Haering CH (2005) The structure and function of SMC and kleisin complexes. Annu Rev Biochem 74: 595–648 [DOI] [PubMed] [Google Scholar]
  47. Nonaka N, Kitajima T, Yokobayashi S, Xiao G, Yamamoto M, Grewal SIS, Watanabe Y (2002) Recruitment of cohesin to heterochromatic regions by Swi6/HP1 in fission yeast. Nat Cell Biol 4: 89–93 [DOI] [PubMed] [Google Scholar]
  48. Ocampo-Hafalla MT, Katou Y, Shirahige K, Uhlmann F (2007) Displacement and re-accumulation of centromeric cohesin during transient pre-anaphase centromere splitting. Chromosoma 116: 531–544 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Ogiwara H, Ohuchi T, Ui A, Tada S, Enomoto T, Seki M (2007) Ctf18 is required for homologous recombination-mediated double-strand break repair. Nucl Acids Res 35: 4989–5000 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Onn I, Heidinger-Pauli JM, Guacci V, Ünal E, Koshland DE (2008) Sister chromatid cohesion: a simple concept with a complex reality. Annu Rev Cell Dev Biol 24: 105–129 [DOI] [PubMed] [Google Scholar]
  51. Petronczki M, Chwalla B, Siomos MF, Yokobayashi S, Helmhart W, Deutschbauer AM, Davis RW, Watanabe Y, Nasmyth K (2004) Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-α-associated protein Ctf4 is essential for chromatid disjunction during meiosis II. J Cell Sci 117: 3547–3559 [DOI] [PubMed] [Google Scholar]
  52. Rankin S, Ayad NG, Kirschner MW (2005) Sororin, a substrate of the anaphase-promoting complex, is required for sister chromatid cohesion in vertebrates. Mol Cell 18: 185–200 [DOI] [PubMed] [Google Scholar]
  53. Rowland BD et al. (2009) Building sister chromatid cohesion: Smc3 acetylation counteracts an antiestablishment activity. Mol Cell 33: 763–774 [DOI] [PubMed] [Google Scholar]
  54. Ryu M-J, Kim B-J, Lee J-W, Lee M-W, Choi H-K, Kim S-T (2006) Direct interaction between cohesin complex and DNA replication machinery. Biochem Biophys Res Commun 341: 770–775 [DOI] [PubMed] [Google Scholar]
  55. Schmidt CK, Brookes N, Uhlmann F (2009) Conserved features of cohesin binding along fission yeast chromosomes. Genome Biol 10: R52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Schmitz J, Watrin E, Lénárt P, Mechtler K, Peters J-M (2007) Sororin is required for stable binding of cohesin to chromatin and for sister chromatid cohesion in interphsae. Curr Biol 17: 630–636 [DOI] [PubMed] [Google Scholar]
  57. Sjögren C, Nasmyth K (2001) Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr Biol 11: 991–995 [DOI] [PubMed] [Google Scholar]
  58. Skibbens RV (2004) Chl1p, a DNA helicase-like protein in budding yeast, functions in sister-chromatid cohesion. Genetics 166: 33–42 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Skibbens RV, Corson LB, Koshland D, Hieter P (1999) Ctf7p is essential for sister chromatid cohesion and links mitotic chromosome structure to the DNA replication machinery. Genes Dev 13: 307–319 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Ström L, Karlsson C, Betts Lindroos H, Wedahl S, Katou Y, Shirahige K, Sjögren C (2007) Postreplicative formation of cohesion is required for repair and induced by a single DNA break. Science 317: 242–245 [DOI] [PubMed] [Google Scholar]
  61. Ström L, Lindroos HB, Shirahige K, Sjögren C (2004) Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair. Mol Cell 16: 1003–1015 [DOI] [PubMed] [Google Scholar]
  62. Sutani T, Kawaguchi T, Kanno R, Itoh T, Shirahige K (2009) Budding yeast Wpl1(Rad61)-Pds5 complex counteracts sister chromatid cohesion-establishing reaction. Curr Biol 19: 492–497 [DOI] [PubMed] [Google Scholar]
  63. Tanaka H, Katou Y, Yagura M, Saitoh K, Itoh T, Araki H, Bando M, Shirahige K (2009) Ctf4 coordinates the progression of helicase and DNA polymerase α. Genes Cells 14: 807–820 [DOI] [PubMed] [Google Scholar]
  64. Tóth A, Ciosk R, Uhlmann F, Galova M, Schleiffer A, Nasmyth K (1999) Yeast Cohesin complex requires a conserved protein, Eco1p (Ctf7), to establish cohesion between sister chromatids during DNA replication. Genes Dev 13: 320–333 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Tougu K, Marians KJ (1996) The interaction between helicase and primase sets the replication fork clock. J Biol Chem 271: 21398–21405 [DOI] [PubMed] [Google Scholar]
  66. Uhlmann F, Nasmyth K (1998) Cohesion between sister chromatids must be established during DNA replication. Curr Biol 8: 1095–1101 [DOI] [PubMed] [Google Scholar]
  67. Uhlmann F, Wernic D, Poupart M-A, Koonin EV, Nasmyth K (2000) Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast. Cell 103: 375–386 [DOI] [PubMed] [Google Scholar]
  68. Ünal E, Heidinger-Pauli JM, Kim W, Guacci V, Onn I, Gygi SP, Koshland DE (2008) A molecular determinant for the establishment of sister chromatid cohesion. Science 321: 566–569 [DOI] [PubMed] [Google Scholar]
  69. Ünal E, Heidinger-Pauli JM, Koshland D (2007) DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science 317: 245–248 [DOI] [PubMed] [Google Scholar]
  70. Warren CD, Eckley EM, Lee MS, Hanna JS, Hughes A, Peyser B, Jie C, Irizarry R, Spencer FA (2004) S-phase checkpoint genes safeguard high-fidelity sister chromatid cohesion. Mol Biol Cell 15: 1724–1735 [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Weitzer S, Lehane C, Uhlmann F (2003) A model for ATP hydrolysis-dependent binding of cohesin to DNA. Curr Biol 13: 1930–1940 [DOI] [PubMed] [Google Scholar]
  72. Xu H, Boone C, Brown GW (2007) Genetic dissection of parallel sister-chromatid cohesion pathways. Genetics 176: 1417–1429 [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Xu H, Boone C, Klein HL (2004) Mrc1 is required for sister chromatid cohesion to aid in recombination repair of spontaneous damage. Mol Cell Biol 24: 7082–7090 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Yuen KWY, Warren CD, Chen O, Kwok T, Hieter P, Spencer FA (2007) Systematic genome instability screens in yeast and their potential relevance to cancer. Proc Natl Acad Sci USA 104: 3925–3930 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Zhang J et al. (2008) Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast. Mol Cell 31: 143–151 [DOI] [PubMed] [Google Scholar]
  76. Zhu W, Ukomadu C, Jha S, Senga T, Dhar SK, Wohlschlegel JA, Nutt LK, Kornbluth S, Dutta A (2007) Mcm10 and And-1/CTF4 recruit DNA polymerase α to chromatin for initiation of DNA replication. Genes Dev 21: 2288–2299 [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from EMBO Reports are provided here courtesy of Nature Publishing Group

RESOURCES