The cohesin complex: structure and principles of interaction with dna

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Abstract

Accurate duplication and separation of long linear genomic DNA molecules is associated with a number of purely mechanical problems. SMC complexes are key components of the cellular machinery that ensures decatenation of sister chromosomes and compaction of genomic DNA during division. Cohesin, one of the essential eukaryotic SMC complexes, has a typical ring structure with intersubunit pore through which DNA molecules can be threaded. The capacity of cohesin for such topological entrapment of DNA is crucial for the phenomenon of post-replicative association of sister chromatids better known as cohesion. Recently, it became apparent that cohesin and other SMC complexes are in fact motor proteins with a very peculiar movement pattern leading to the formation of DNA loops. This specific process was called loop extrusion. Extrusion underlies multiple cohesin’s functions beyond cohesion, but the molecular mechanism of the process remains a mystery. In this review, we have summarized data on the molecular architecture of cohesin, the influence of ATP hydrolysis cycle on this architecture, and the known modes of cohesin–DNA interactions. Many of the seemingly disparate facts presented here will probably be incorporated in a unified mechanistic model of loop extrusion in a not so far future.

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About the authors

A. K. Golov

Institute of Gene Biology, Russian Academy of Sciences; Technion – Israel Institute of Technology

Author for correspondence.
Email: golovstein@gmail.com
Russian Federation, Moscow; Haifa, Israel

A. A. Gavrilov

Институт биологии гена РАН

Email: aleksey.a.gavrilov@gmail.com
Russian Federation, Москва

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2. Fig. 1. Sister chromatid cohesion and DNA loop extrusion mediated by SMC complexes. a – Two basic cohesin activities: cohesion (1) and extrusion (2). b – Extrusion mediated by SMC complexes and the activity of type II DNA topoisomerases mediate post-replicative individualization of sister genomes in all cells, prokaryotic and eukaryotic.

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3. Fig. 2. Subunit structure of the cohesin complex. a – Folding and main structural features of SMC proteins. b – General structure of the three-part cohesin ring and interaction of HAWK subunits with it. c – General structure of hook-shaped HAWK subunits of SMC complexes

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4. Fig. 3. Diversity of conformational states of cohesin. a – O-, E- and J-configurations of cohesin head domains and transitions between them, RAD21 subunit is not shown for clarity of the figure. The pictograms indicate the S-K ring and subcompartments (E-S, E-K and J-K) formed by the interaction of the head domains with each other. b – Main conformational states of cohesin, revealed using microscopic methods

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5. Fig. 4. Topological interaction of the cohesin ring with DNA. a – Topological (1) and pseudo-topological (2) interaction of cohesin with DNA. The pictograms use ● and + symbols to reflect the direction of the DNA strand passing through the plane of the figure; topological binding is indicated by the gray fill. b – Methods for identifying the topological nature of the interaction between the protein complex and DNA: analysis of the stability of binding in buffers with high ionic strength (1); analysis of the sensitivity of the interaction to proteolytic cleavage of one of the subunits (2); analysis of sensitivity to a break in the DNA molecule (3); analysis of the stability of the interaction under denaturing conditions after covalent cross-linking of the protein ring using cysteine-specific cross-linking agents (BMOE, bBBr) (4). c – Two pathways for removing the cohesin ring from DNA, realized in eukaryotic cells: WAPL-dependent (1) and proteolytic (2)

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6. Fig. 5. Electrostatic interactions of cohesin with DNA. a – Two hypothetical pathways of “DNA capture” formation proposed to describe the activity of cohesin in S. cerevisiae (1) and Schizosaccharomyces pombe (2). The pictograms use ● and + symbols to reflect the direction of DNA strand passage through the plane of the figure; topological binding is indicated by gray filling. The pairs of pictograms show the formation of E-S and E-K subcompartments and the position of DNA strands relative to them on the left one, and the position of DNA strands relative to the S-K ring on the right one. The dotted parts of the RAD21 subunit correspond to the regions in which the path of the protein chain is shown conditionally for clarity of the figure (in reality, the HAWK subunits remain bound to RAD21 at all stages shown). b – Electrostatic interactions of the loop domains of cohesin with DNA. Three (non-mutually exclusive) scenarios are shown: NIPBL-subunit-mediated interaction (1), direct DNA contact with the inner surface of the loop domain pore (2), and direct DNA contact with the south pole of the loop domain dimer (3). c – Interaction of the HAWK-B subunits of cohesin (STAG1/2) and condensin (CAP-G) with DNA. A peptide loop, called a “safety belt”, formed by the kleisin subunit of condensin (CAP-H), additionally stabilizes the binding of the HAWK-B subunit (CAP-G) to DNA.

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