Cohesion and cohesin-dependent chromatin organization
Introduction
Cohesin is a ring-shaped protein complex comprising four core subunits, Smc1, Smc3, Scc1/Rad21, and stromal antigen (SA)/STAG, and is conserved among eukaryotes (Figure 1) [1,2]. Cohesin is essential but not sufficient for sister chromatid cohesion, for which several regulatory proteins are required. For instance, cohesin is loaded on chromatin before DNA replication through a cohesin loader Scc2/Nipbl-Scc4/Mau2, and cohesion is established during DNA replication in S phase. For cohesion establishment, acetylation of Smc3 by acetyltransferases Eco1/Esco/Deco and, in metazoans, loading of a cohesin-binding protein Sororin/Dalmatian are essential. Sororin is recruited on chromatin-bound cohesin in a Smc3 acetylation-dependent manner. These Sororin and Smc3 acetylation antagonize the function of ‘anti-establishment factors’ Wapl and Pds5, both being cohesin-binding proteins, to establish cohesion [3]. In addition to sister chromatid cohesion, numerous recent studies have investigated another aspect of cohesin function in regulating higher order chromatin structure. This review summarizes recent progress in the understanding of how cohesion is achieved and further discusses cohesin-mediated organization of chromatin structure.
Section snippets
Cohesin loading and establishment of cohesion
One of the most remarkable features of cohesin is topological entrapment of DNA. It is clear at least that a cohesin loader Scc2-Scc4 and ATPase activity of cohesin are required for its loading [4, 5, 6]. However, it is still debatable as to how DNA enters the cohesin ring during loading. Currently, two possibilities have been suggested regarding the entry gate on the cohesin ring (Figure 2). One possibility is opening of the Smc1-Smc3 hinge interface to load DNA. Evidence supporting this
Cohesin and higher-order chromatin architecture
Recent technical advances in chromosome conformation capture-sequencing methods including 3C, 4C, 5C, Hi-C, or ChIA-PET accelerated studies of higher-order chromatin structure. In particular, Hi-C has enabled the identification of higher-order genome-wide chromatin interactions [30, 31, 32]. Although the nomenclature of topologically associated domains (TADs), sub-TADs, or loops is not yet well defined [31], a high resolution Hi-C study of several kilobase (kb) resolution has identified ∼10,000
Single molecule dynamics of cohesin
Accumulating evidence for cohesin localization on the genome and chromatin structures in 3C and Hi-C studies have suggested that cohesin is a motor protein that extrudes DNA loops. However, there is no evidence showing the motor activity of cohesin so far. Recent studies on cohesin single-molecule observations directly addressed this issue and unveiled the cohesin dynamics on DNA.
One of the most important questions is whether cohesin has a motor activity. If indeed the case, cohesin must be
Conclusion and perspective
Accumulating evidence from yeast genetics, biochemistry, and cell biology have revealed the mechanism underlying sister chromatid cohesion, ever since the discovery of SMC proteins. Nevertheless, fundamental questions regarding the mechanism of cohesion establishment or cause of cohesinopathies are yet unsolved. Technical improvement of resolution in time and space in future studies would help further these understandings. Observation of cohesin-regulated higher-order chromatin structures at
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The author would like to thank numerous colleagues in the field, for their insightful discussions. The author apologizes to many colleagues whose studies could not be cited because of space limitation. Studies in the author’s laboratory were chiefly supported by JST-PRESTO (25-J-J4301) and JSPS Grant-in-Aid for Young Scientists (25711002).
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