SMC complexes: Lifting the lid on loop extrusion

Abstract

Loop extrusion has emerged as a prominent hypothesis for how SMC complexes shape chromosomes - single molecule in vitro observations have yielded fascinating images of this process. When not extruding loops, SMC complexes are known to topologically entrap one or more DNAs. Here, we review how structural insight into the SMC complex cohesin has led to a molecular framework for both activities: a Brownian ratchet motion, associated with topological DNA entry, might repeat itself to elicit loop extrusion. After contrasting alternative loop extrusion models, we explore whether topological loading or loop extrusion is more adept at explaining in vivo SMC complex function. SMC variants that experimentally separate topological loading from loop extrusion will in the future probe their respective contributions to chromosome biology.

Figure 1

Molecular model for topological DNA entry into the cohesin ring. a) Structural overview of the cohesin complex components, as well as of the cohesin loader, and their assembly. b) Model for DNA entry into the cohesin ring through the kleisin N-gate followed, or not, by ATPase head gate passage.

Figure 2

A Brownian ratchet model for loop extrusion by cohesin. a) Repeated cycles of gripping-to-slipping state transitions, followed by DNA release from the Scc3-hinge module, enact a ratchet that drives loop extrusion. b) Three scenarios of how DNA could engage with the cohesin complex during loop extrusion, resulting in a topological, pseudo-topological or non-topological interaction.

Figure 3

Alternative models for loop extrusion by SMC complexes. a) The tethered inchworm model, in which the two HEAT-repeat subunits (HEAT) step along the DNA. b) The segment capture model, inspired by prokaryotic SMC complexes, in which the Kite subunits (Kite) perform a power stroke to loop DNA. An additional DNA anchor (not shown) is required for loop extrusion. c) The scrunching model suggests that the hinge captures DNA and hands it over to the heads to enlarge the loop.

Figure 4

Challenges to in vivo DNA loop extrusion. a) DNA-bound obstacles and sparse free DNA must be navigated by advancing SMC complexes. b) Condensin extrudes DNA asymmetrically, leaving gaps during chromosome formation. c) Long stretches of chromatin must be extruded, where diffusion capture offers shortcuts. d) Loop extrusion solely generates intra-chromosomal cis loops, while SMC complexes also engage in inter-chromosomal interactions. e) Loop extrusion predicts formation of a linear SMC backbone. SMC complexes are observed to form clusters, as expected from diffusion capture.