Cohesin-dependent loop extrusion: molecular mechanics and role in cell physiology

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Abstract

The most prominent representatives of multisubunit SMC-complexes, cohesin and condensin, are best known as structural components of mitotic chromosomes. It turned out that these complexes, as well as their bacterial homologues, are molecular motors, the ATP-dependent movement of these complexes along DNA threads leads to the formation of DNA loops. In recent years, we have witnessed an avalanche-like accumulation of data on the process of SMC-dependent DNA looping, also known as loop extrusion. This review briefly summarizes the current understanding of the place and role of cohesin-dependent extrusion in cell physiology and presents a number of models describing the potential molecular mechanism of extrusion in a most compelling way. We conclude the review with a discussion of how the capacity of cohesin to extrude DNA loops may be mechanistically linked to its involvement in sister chromatid cohesion.

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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

Institute of Gene Biology, Russian Academy of Sciences

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

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2. Fig. 1. The structure of cohesin and its involvement in the cohesion of sister chromatids. a – Topological attachment of cohesin rings to sister chromatids during cohesion. b – Scheme of the core trimer forming the cohesin ring; recruitment of additional HAWK subunits to the core trimer. c – Dimerization of the head domains of SMC subunits required for ATP hydrolysis

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3. Fig. 2. Cohesin activity throughout the cell cycle and the result of chromatin compaction by SMC-dependent extrusion. a – The number of intact cohesin complexes and their activity during the mitotic cycle in vertebrate cells (1) and S. cerevisiae (2). b – Vertebrate metaphase chromosomes formed by the extrusion activity of condensin, which accumulates in the axial structures. The typical X-shaped structure is maintained by residual centromeric cohesion of two metacentric sister chromosomes. c – Compact chromatid-like structures of the “vermicelli” type formed in vertebrate interphase cells by cohesin-dependent extrusion upon suppression of WAPL activity. Cohesin is the main structural component of the axial structures of such chromosomes.

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4. Fig. 3. Mechanisms of cohesin-dependent extrusion arrest and chromatin folding patterns resulting from blocking and stabilizing extrusion complexes. a – CAR-dependent and CTCF-dependent extrusion arrest. Cohesin engagement with a single site likely converts bidirectional cohesin-dependent extrusion into unidirectional. ESCO1 (Eco1)-dependent acetylation of the SMC3 subunit (SMC3 acetylation is shown as a yellow dot) plays an important role in extrusion arrest and protection of the arrested complex from WAPL. b – Structural loops containing CAR or CTCF sites in the bases are formed due to complete (bidirectional) extrusion arrest. SMC3 acetylation is shown as a yellow dot. c – The position of CAR and CTCF sites in the genome determines the formation of characteristic supranucleosomal patterns of chromatin folding: structural loops and topologically associated domains

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5. Fig. 4. Features of cohesin-dependent extrusion in the vicinity of a double-strand break (according to Arnould et al. [102]). The appearance of double-strand breaks (1, 2) leads to the emergence of new sites of cohesin-dependent extrusion arrest at the break site (3), the spread of the γH2AX signal from the break site along the topological domain due to unidirectional extrusion (3–5), and the displacement of break sites into the chromosomal territory (5).

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6. Fig. 5. Molecular aspects of SMC-dependent extrusion. a – Bidirectional extrusion carried out by cohesin monomers (1) and unidirectional extrusion carried out by condensin complexes (2). The “safety belt” most likely takes direct part in stabilizing one of the bases of the loop being formed during condensin-dependent extrusion. b – Hypothetical variants of the binding modality of the SMC complex to the DNA of the growing loop during extrusion

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7. Fig. 6. Cohesin-dependent extrusion by the coalescence/pumping mechanism. a – Pseudo-topological extrusion by the coalescence/pumping mechanism (according to the Hearing group [126]). b – Non-topological extrusion by the coalescence/pumping mechanism (according to Oldenkamp and Rowland [10]). c – Exchange of two bases of the growing loop during pseudo-topological extrusion can provide frequent switching of the direction of movement and manifest itself as an apparent bidirectionality of the process. In all panels, the pictograms reflect the path of the DNA strand, with the ● and + symbols reflecting the direction of passage of the DNA strand through the plane of the cohesin ring. DNA regions that are or were dynamic bases of the loop in previous stages are shown in red, anchor regions are shown in blue. The dotted regions in the middle of the DNA strand reflect the fundamentally unlimited size of the growing loops.

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8. Fig. 7. Cohesin-dependent extrusion by bending the “elbows”. a – Extrusion by the Brownian ratchet mechanism (according to Higashi et al. [127]). b – Extrusion by the “row-catch” mechanism (according to Bauer et al. [124]). 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 associated with RAD21 at all stages shown). Other designations are as in Fig. 6

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9. Fig. 8. Schematic of a hypothetical molecular cascade linking the process of cohesin-dependent extrusion and the establishment of cohesion. a – The originally proposed cascade scheme: coupling of topological loading of cohesin onto DNA with the initiation of extrusion. b – Modified cascade scheme taking into account the accumulated structural data on the extrusion process: coupling of topological loading of cohesin with the termination of extrusion. The central place in the switch between extrusion and topological attachment is occupied by the “DNA-capture” configuration.

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