Three-Dimensional Loop Extrusion

Bonato, Andrea; Michieletto, Davide

doi:10.1101/2021.08.28.458013

Cited by 5 publications

(7 citation statements)

References 60 publications

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“…To more firmly establish that the semi-flexible polymeric nature of the DNA is a key determinant of the force-dependent DNA step sizes, we performed Molecular Dynamics simulations (MD) based on a generalized version of the well-known loop-extrusion model that can perform extrusion by grabbing segments of DNA that are non-contiguous (32). In the simulated model (see Methods), one end of a 1.5…”

Section: Condensin Extrudes Dna In Steps Of Tens Of Nm Reeling In Hundreds Of Base Pairs Per Stepmentioning

confidence: 99%

Condensin extrudes DNA loops in steps up to hundreds of base pairs that are generated by ATP binding events

Ryu

Rah

Janissen

et al. 2020

Preprint

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The condensin SMC protein complex organizes chromosomal structure by extruding loops of DNA. Its ATP-dependent motor mechanism remains unclear but likely involves steps associated with large conformational changes within the ~50 nm protein complex. Here, using magnetic tweezers, we resolve single steps in loop extrusion by individual yeast condensins. Step sizes range between 20-45 nm at forces of 1.0-0.2 pN, respectively, comparable to the complex size. The large steps show that condensin reels in DNA in very sizeable amounts, up to ~600 bp per extrusion step, consistent with the non-stretched DNA polymer at these low forces. Using ATP-binding-impaired and ATP-hydrolysis-deficient mutants, we find that ATP binding is the primary step-generating stage underlying DNA loop extrusion. We discuss the findings in terms of a scrunching model where a stepwise DNA loop extrusion is generated by an ATP-binding-induced engagement of the hinge and the globular domain of the SMC complex.

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Section: Condensin Extrudes Dna In Steps Of Tens Of Nm Reeling In Hundreds Of Base Pairs Per Stepmentioning

confidence: 99%

Condensin extrudes DNA loops in steps up to hundreds of base pairs that are generated by ATP binding events

Ryu

Rah

Janissen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…This suggests elbow bending being a feature arising from divergent evolution, rather than being a feature fundamental to translocation and loop extrusion (20, 27, 52). We also note that scrunching and other SMCC-walking-based models (49) have difficulty generating steps along DNA that are larger than the complex itself, as has been observed for SMCCs (53); in contrast steps larger than the SMCC itself occur naturally in models that are based on DNA loop capture (41, 45).…”

Section: Introductionmentioning

confidence: 66%

“…The basic DNA-segment-capture mechanism (41) qualitatively explains existing experiments on SMCC translocation along DNA, and subsequent theoretical work incorporating similar mechanisms involving binding at one DNA site with capture of a second, distant DNA (45, 46) has led to concordant results. An alternative ‘scrunching’ model has also been proposed, based on the idea that DNA might be handed over from the hinge to the heads (or vice versa) via folding of the SMCC at an “elbow” joint (35, 47, 48, 49).…”

Section: Introductionmentioning

confidence: 76%

“…Left: Composite structural model of bsSMC (19), showing the two SMC proteins in cyan and green, the dimerization "hinge" domain (top, PDB structure 4RSJ), the long coiled-coiled arms (PDB 5XG2 and 5NNV) with putative "elbow" domain, and ATP-binding/ATPase "heads" (PDB 5XEI). The basic DNA-segment-capture mechanism (41) qualitatively explains existing experiments on SMCC translocation along DNA, and subsequent theoretical work incorporating similar mechanisms involving binding at one DNA site with capture of a second, distant DNA (45,46) has led to concordant results. An alternative 'scrunching' model has also been proposed, based on the idea that DNA might be handed over from the hinge to the heads (or vice versa) via folding of the SMCC at an "elbow" joint (35,47,48,49).…”

Section: Introductionmentioning

confidence: 80%

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DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations

Nomidis

Carlon

Gruber

et al. 2021

Preprint

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Structural Maintenance of Chromosomes (SMC) protein complexes play essential roles in genome folding and organization across all domains of life. In order to determine how the activities of these large (about 50 nm) complexes are controlled by ATP binding and hydrolysis, we have developed a molecular dynamics (MD) model that realistically accounts for thermal conformational motions of SMC and DNA. The model SMCs make use of DNA flexibility and looping, together with an ATP-induced "power stroke", to capture and transport DNA segments, so as to robustly translocate along DNA. This process is sensitive to DNA tension: at low tension (about 0.1 pN), the model performs steps of roughly 60 nm size, while, at higher tension, a distinct inchworm-like translocation mode appears, with steps that depend on SMC arm flexibility. By permanently tethering DNA to an experimentally-observed additional binding site ("safety belt"), the same model performs loop extrusion. We find that the dependence of loop extrusion on DNA tension is remarkably different when DNA tension is fixed vs when DNA end points are fixed: Loop extrusion reversal occurs above 0.5 pN for fixed tension, while loop extrusion stalling without reversal occurs at about 2 pN for fixed end points. Our model quantitatively matches recent experimental results on condensin and cohesin, and makes a number of clear predictions. Finally we investigate how specific structural changes affect the SMC function, which is testable in experiments on varied or mutant SMCs.

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“…To test this idea, we examine simulated three-point contact data from the full MaxEnt model constrained by Hi-C experiments [20] (Figure 2A); and a model of loop-extruding condensins on a bacterial chromosome [7] (Figure 2B). We expect alternative simulation schemes for loop-extrusion [25, 26] to yield similar results, as long as loop-extruders interact weakly and/or rarely. We base both simulations on the chromosome of Caulobacter crescentus , a well-studied model organism with one circular chromosome over 4 Mb in length.…”

Section: Resultsmentioning

confidence: 99%

Physical models for chromosome organization to predict multi-contact statistics

Harju

Messelink

Broedersz

2022

Preprint

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Whereas pairwise Hi-C methods have taught us much about chromosome organization, new multi-contact methods, such as single-cell Hi-C, hold promise for identifying higher-order loop structures. The presence of such high-order structure may be revealed by comparing multi-contact data with a theoretical prediction based on pairwise contact information. Here, we develop and compare three polymer-based prediction schemes for chromosomal three-point contact frequencies, based on a non-interacting polymer, a polymer with independent cross-linking, and a polymer with weak pairwise interactions between monomers. First, we test these predictions for two distinct simulation models of bacterial chromosome organization: a data-driven model inferred from a Hi-C map and bottom-up simulations of loop-extruding proteins. We find that the most predictive approximation is indicative of how contacts are primarily formed in a model. We then apply our prediction schemes to previously published super-resolution chromatin tracing data for human IMR90 cells. Strikingly, we find that the best prediction is given by the independent cross-linking approximation. This result is consistent with chromosomal contacts being dominantly caused by weakly interacting loop-extruders. Our work could have implications for developing models of chromosome organization from multi-contact data, and for better identifying higher-order loop structures.

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Three-Dimensional Loop Extrusion

Cited by 5 publications

References 60 publications

Condensin extrudes DNA loops in steps up to hundreds of base pairs that are generated by ATP binding events

Condensin extrudes DNA loops in steps up to hundreds of base pairs that are generated by ATP binding events

DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations

Physical models for chromosome organization to predict multi-contact statistics

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