SMC complexes: Lifting the lid on loop extrusion

Higashi, Torahiko L.; Uhlmann, Frank

doi:10.1016/j.ceb.2021.12.003

Cited by 38 publications

(43 citation statements)

References 79 publications

(110 reference statements)

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“…( 67 ) is topologically equivalent to the variant of loop extrusion for the segment-capture model shown in Figure 7B in Ref. ( 42 ) and Figure 6B of this paper, all with an initial loop of DNA passing twice through the lower compartment, a subsequent ATP-binding-driven ‘power stroke’ guiding upstream DNA segment capture in the upper compartment, and then ATP hydrolysis and Walker ATPase separation which causes enlargement of the initial DNA loop by merging it with the captured DNA segment ( 83 )).…”

Section: Discussionmentioning

confidence: 97%

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

Nomidis

Carlon

Gruber

et al. 2022

Nucleic Acids Research

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Structural Maintenance of Chromosomes (SMC) complexes play essential roles in genome organization across all domains of life. To determine how the activities of these large (≈50 nm) complexes are controlled by ATP binding and hydrolysis, we developed a molecular dynamics model that accounts for conformational motions of the SMC and DNA. The model combines DNA loop capture with an ATP-induced ‘power stroke’ to translocate the SMC complex along DNA. This process is sensitive to DNA tension: at low tension (0.1 pN), the model makes loop-capture steps of average 60 nm and up to 200 nm along DNA (larger than the complex itself), while at higher tension, a distinct inchworm-like translocation mode appears. By tethering DNA to an experimentally-observed additional binding site (‘safety belt’), the model SMC complex can perform loop extrusion (LE). The dependence of LE on DNA tension is distinct for fixed DNA tension vs. fixed DNA end points: LE reversal occurs above 0.5 pN for fixed tension, while LE stalling without reversal occurs at about 2 pN for fixed end points. Our model matches recent experimental results for condensin and cohesin, and makes testable predictions for how specific structural variations affect SMC function.

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Section: Discussionmentioning

confidence: 97%

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

Nomidis

Carlon

Gruber

et al. 2022

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…(41) and Fig. 6B of this paper, all with an initial loop of DNA passing twice through the lower compartment, a subsequent ATP-binding-driven “power stroke” guiding upstream DNA segment capture in the upper compartment, and then ATP hydrolysis and Walker ATPase separation which causes enlargement of the initial DNA loop by merging it with the captured DNA segment (82)).…”

Section: Discussionmentioning

confidence: 93%

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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“…Loop extrusion by condensins has been observed not only in an experimental setup made of purified proteins but also in a mitotic egg extract [ 74 ]. During the past years, several molecular mechanisms have been proposed for condensin-mediated loop extrusion (see reviews [ 75 , 76 , 77 , 78 ]). How positive supercoils and loops on a long stretch of genomic DNA, which are created by condensins, result in highly organized structures of mitotic chromosomes is one of the biggest open questions.…”

Section: Our Current Understanding Of Major Chromosome-associated Pro...mentioning

confidence: 99%

Making Mitotic Chromosomes in a Test Tube

Shintomi

2022

Epigenomes

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Mitotic chromosome assembly is an essential preparatory step for accurate transmission of the genome during cell division. During the past decades, biochemical approaches have uncovered the molecular basis of mitotic chromosomes. For example, by using cell-free assays of frog egg extracts, the condensin I complex central for the chromosome assembly process was first identified, and its functions have been intensively studied. A list of chromosome-associated proteins has been almost completed, and it is now possible to reconstitute structures resembling mitotic chromosomes with a limited number of purified factors. In this review, I introduce how far we have come in understanding the mechanism of chromosome assembly using cell-free assays and reconstitution assays, and I discuss their potential applications to solve open questions.

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SMC complexes: Lifting the lid on loop extrusion

Cited by 38 publications

References 79 publications

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

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

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

Making Mitotic Chromosomes in a Test Tube

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