Bridging-induced phase separation induced by cohesin SMC protein complexes

Ryu, Je-Kyung; Bouchoux, Céline; Liu, Hon Wing; Kim, Eugene; Minamino, Masashi; Groot, Ralph de; Katan, Allard J.; Bonato, Andrea; Marenduzzo, Davide; Michieletto, Davide; Uhlmann, Frank; Dekker, Cees

doi:10.1126/sciadv.abe5905

Cited by 128 publications

(170 citation statements)

References 60 publications

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“…In solution under less controlled conditions, however, cohesin loading leads to cluster formation on DNA, promoting biomolecular condensations as observed by atomic force microscopy [108]. A very recent study discovered bridging-induced phase separation when working with DNA molecules that exceed 3 kb [108]. In vivo observations confirm that a subpopulation of cohesin molecules appears to associate with chromatin in a separated phase, consistent with previous observations of cohesin clustering observed in vivo [109][110][111].…”

Section: Figuresupporting

confidence: 84%

“…This implies that DHs, which are loaded onto replication origins together with cohesin in G1, can function to partially limit cohesin diffusion away from replication start sites. In solution under less controlled conditions, however, cohesin loading leads to cluster formation on DNA, promoting biomolecular condensations as observed by atomic force microscopy [108]. A very recent study discovered bridging-induced phase separation when working with DNA molecules that exceed 3 kb [108].…”

Section: Figurementioning

confidence: 99%

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Towards a Structural Mechanism for Sister Chromatid Cohesion Establishment at the Eukaryotic Replication Fork

Henrikus

Costa

2021

Biology

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Cohesion between replicated chromosomes is essential for chromatin dynamics and equal segregation of duplicated genetic material. In the G1 phase, the ring-shaped cohesin complex is loaded onto duplex DNA, enriching at replication start sites, or “origins”. During the same phase of the cell cycle, and also at the origin sites, two MCM helicases are loaded as symmetric double hexamers around duplex DNA. During the S phase, and through the action of replication factors, cohesin switches from encircling one parental duplex DNA to topologically enclosing the two duplicated DNA filaments, which are known as sister chromatids. Despite its vital importance, the structural mechanism leading to sister chromatid cohesion establishment at the replication fork is mostly elusive. Here we review the current understanding of the molecular interactions between the replication machinery and cohesin, which support sister chromatid cohesion establishment and cohesin function. In particular, we discuss how cryo-EM is shedding light on the mechanisms of DNA replication and cohesin loading processes. We further expound how frontier cryo-EM approaches, combined with biochemistry and single-molecule fluorescence assays, can lead to understanding the molecular basis of sister chromatid cohesion establishment at the replication fork.

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Section: Figuresupporting

confidence: 84%

Section: Figurementioning

confidence: 99%

Towards a Structural Mechanism for Sister Chromatid Cohesion Establishment at the Eukaryotic Replication Fork

Henrikus

Costa

2021

Biology

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“…sible DNA sites clustering together in 3D space. Clustering arising through the bridging-induced attraction has recently been found in vitro for systems of DNA and cohesin (which binds multivalently to DNA) [31].…”

Section: Resultsmentioning

confidence: 99%

Complex small-world regulatory networks emerge from the 3D organisation of the human genome

Brackley

Gilbert

Michieletto

et al. 2021

Preprint

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The discovery that overexpressing one or a few critical transcription factors can switch cell state suggests that gene regulatory networks are relatively simple. In contrast, genome-wide association studies (GWAS) point to complex phenotypes being determined by hundreds of loci that rarely encode transcription factors and which in- dividually have small effects. Here, we use computer simulations and a simple fitting-free polymer model of chromosomes to show that spatial correlations arising from 3D genome organisation naturally lead to stochastic and bursty transcription as well as complex small-world regulatory networks (where the transcriptional activity of each genomic region subtly affects almost all others). These effects require factors to be present at sub-saturating levels; increasing levels dramatically simplifiies networks as more transcription units are pressed into use. Consequently, results from GWAS can be reconciled with those involving overexpression. We apply this pan-genomic model to predict patterns of transcriptional activity in whole human chromosomes, and, as an example, the effects of the deletion causing the diGeorge syndrome.

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“…It has been shown in vitro that purified condensin hydrolyses ATP to extrude loops of naked DNA (Ganji et al, 2018;Kong et al, 2020), but the structural details of the formation and enlargement of such loops remain poorly understood . Furthermore, whether such loop extrusion activity is the only way that condensin complexes organize mitotic chromosomes is still under debate as condensins and other architectural proteins may also participate in the organization of chromosomes by bridging-induced phase separation (Cheng et al, 2015;Sakai et al, 2018;Ryu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

RNA polymerase backtracking results in the accumulation of fission yeast condensin at active genes

et al. 2021

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The mechanisms leading to the accumulation of the SMC complexes condensins around specific transcription units remain unclear. Observations made in bacteria suggested that RNA polymerases (RNAPs) constitute an obstacle to SMC translocation, particularly when RNAP and SMC travel in opposite directions. Here we show in fission yeast that gene termini harbour intrinsic condensin-accumulating features whatever the orientation of transcription, which we attribute to the frequent backtracking of RNAP at gene ends. Consistent with this, to relocate backtracked RNAP2 from gene termini to gene bodies was sufficient to cancel the accumulation of condensin at gene ends and to redistribute it evenly within transcription units, indicating that RNAP backtracking may play a key role in positioning condensin. Formalization of this hypothesis in a mathematical model suggests that the inclusion of a sub-population of RNAP with longer dwell-times is essential to fully recapitulate the distribution profiles of condensin around active genes. Taken together, our data strengthen the idea that dense arrays of proteins tightly bound to DNA alter the distribution of condensin on chromosomes.

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Bridging-induced phase separation induced by cohesin SMC protein complexes

Cited by 128 publications

References 60 publications

Towards a Structural Mechanism for Sister Chromatid Cohesion Establishment at the Eukaryotic Replication Fork

Towards a Structural Mechanism for Sister Chromatid Cohesion Establishment at the Eukaryotic Replication Fork

Complex small-world regulatory networks emerge from the 3D organisation of the human genome

RNA polymerase backtracking results in the accumulation of fission yeast condensin at active genes

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