Cohesin loading and sliding

Abstract

SummaryCohesin is best known as a crucial component of chromosomal stability. Composed of several essential subunits in budding yeast, cohesin forms a ring-like complex that is thought to embrace sister chromatids, thereby physically linking them until their timely segregation during cell division. The ability of cohesin to bind chromosomes depends on the Scc2-Scc4 complex, which is viewed as a loading factor for cohesin onto DNA. Notably, in addition to its canonical function in sister chromatid cohesion, cohesin has also been implicated in gene regulation and development in organisms ranging from yeast to human. Despite its importance, both as a mediator of sister chromatid cohesion and as a modulator of gene expression, the nature of the association of cohesin with chromosomes that enables it to fulfil both of these roles remains incompletely understood. The mechanism by which cohesin is loaded onto chromosomes, and how cohesin and the related condensin and Smc5-Smc6 complexes promote DNA interactions require further elucidation. In this Commentary, we critically review the evidence for cohesin loading and its subsequent apparent sliding along chromosomes, and discuss the implications gained from cohesin localisation studies for its important functions in chromosome biology. Journal of Cell Scienceand lethality. In this case, cohesin is thought to promote transcriptional activity of an ecdysone receptor gene (Pauli et al., 2008;Schuldiner et al., 2008). The requirement for cohesin in differentiated, post-mitotic cells provides clear evidence for a function of cohesin on chromosomes that is distinct from its role in cell division. A recent comprehensive analysis of the consequences of cohesin disruption on gene expression from polytene chromosomes in Drosophila salivary gland cells has revealed a role for cohesin in both the upregulation and downregulation of several genes in the vicinity of its binding sites (Pauli et al., 2010). How cohesin and changes to its expression levels result in distinct transcriptional outcomes at individual gene loci and in different cell types is incompletely understood (Schaaf et al., 2009).In zebrafish, cohesin has been shown to positively regulate the Runx transcription factors, which determine cell fate during early embryonic development. Downregulation of the Scc1 or Smc3 cohesin subunits leads to aberrant expression of Runx proteins in a dose-dependent manner, despite cell division being able to proceed (Horsfield et al., 2007). Finally, in mouse and human cells, cohesin-binding sites on chromosomes significantly overlap with those of the transcriptional insulator CCCTC-binding factor (CTCF) (Parelho et al., 2008;Wendt et al., 2008). This colocalisation is functionally relevant because depletion of cohesin subunits Scc1 or Smc3 recapitulates the loss of insulator function seen after CTCF depletion. Notably, the effect of cohesin on the well-characterised insulator at the H19-Igf2 locus is observed even in the G1 phase of the cell cycle, when sister chromatids are absent. Th...

Nonequilibrium Chromosome Looping via Molecular Slip Links

“…In both cases, the dimer/ring acts as a sliding bridge or molecular slip-link [14,15], and we will use the latter term to describe both cases. In vitro and in vivo experiments show that cohesin does indeed topologically link to DNA (with binding 2 mediated by "loader proteins" such as Scc2 or NIPBL [1,16]), that it can slide along DNA diffusively, and that it remains bound for τ ∼ 20 minutes before dissociating [16][17][18][19][20].…”

“…We start from the observation that the molecular topology of cohesin dimersi.e. that of a slip-link -is compatible with diffusive sliding along DNA or chromatin [17].From this premise, we formulate a non-equilibrium model where the binding and unbinding kinetics of cohesin violates detailed balance, and show that within this context passive sliding is sufficient to account for both the creation of loops of hundreds of kbp before dissociation, and the formation of convergent CTCF-mediated loops. The probability of formation of such loops in our framework differs from the canonical power law decay governing the statistics of equilibrium polymer looping, and is consistent with currently available data on CTCF loops.…”

“…In both cases, the dimer/ring acts as a sliding bridge or molecular slip-link [14,15], and we will use the latter term to describe both cases. In vitro and in vivo experiments show that cohesin does indeed topologically link to DNA (with binding 2 mediated by "loader proteins" such as Scc2 or NIPBL [1,16]), that it can slide along DNA diffusively, and that it remains bound for τ ∼ 20 minutes before dissociating [16][17][18][19][20].One recent attempt to address the mechanism underlying CTCF and cohesin-mediated looping is the "loop extrusion model" which argues that cohesins (or other "loop extruding factors") can actively create loops of 100−1000 kbp by travelling in opposite directions along the chromosome [12,21,22]. This model is appealing because it naturally explains the bias in favour of convergent loops, if the slip-link gets stuck when it finds a CTCF binding site pointing towards it (an assumption consistent with experiments probing CTCF and cohesin binding [8,22,24]).…”

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…148 Cohesin rings encircle two replicated daughter chromatids and thereby maintain, through a topological confinement, the cohesion of chromatids until mitosis. [231][232][233] An endoprotease called separase is activated during mitosis and cleaves the Scc1/Rad21 (kleisin) subunit, thereby opening the ring of cohesin and making chromatid separation possible. In the yeast Saccharomyces cerevisiae, the C-terminal fragment of separase-cleaved Scc1/Rad21 bears N-terminal Arg, a destabilizing residue [ Fig.…”

Cohesin and chromatin organisation

“…An important remaining question concerns the mechanisms that reposition cohesin from its loading sites to its final destination [53]. Transcription appears to drive cohesin repositioning in the budding yeast S. cerevisiae, since cohesin is only excluded from genes as long as they are transcribed.…”