SMC motor proteins extrude DNA asymmetrically and can switch directions
Open accessAbstract
Structural maintenance of chromosomes (SMC) complexes organize the genome via DNA loop extrusion. Although some SMCs were reported to do so symmetrically, reeling DNA from both sides into the extruded DNA loop simultaneously, others perform loop extrusion asymmetrically toward one direction only. The mechanism underlying this variability remains unclear. Here, we examine the directionality of DNA loop extrusion by SMCs using in vitro single-molecule experiments. We find that cohesin and SMC5/6 do not reel in DNA from both sides, as reported before, but instead extrude DNA asymmetrically, although the direction can switch over time. Asymmetric DNA loop extrusion thus is the shared mechanism across all eukaryotic SMC complexes. For cohesin, direction switches strongly correlate with the turnover of the subunit NIPBL, during which DNA strand switching may occur. Apart from expanding by extrusion, loops frequently diffuse and shrink. The findings reveal that SMCs, surprisingly, can switch directions.
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Recent studies have shown that SMCs can switch direction, effectively acting as two-sided extruders.
“recent studies have shown that SMCs can switch direction, effectively acting as two-sided extruders,61”
From Bringing the genetically minimal cell to life on a computer in 4D (2026) · cites this paper as [61]
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- [61]61. Isiaka, B.N. ∙ Semple, J.I. ∙ Haemmerli, A. ... Cohesin forms fountains at active enhancers in C. elegans Preprint at bioRxiv. 2023; Crossref Scopus (0) Google Scholar
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Bringing the genetically minimal cell to life on a computer in 4D
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Shah, R., Tortora, M. M. C., Louafi, N., Rahmaninejad, H., Hansen, K. L., Anderson, E. C., Wen, D., Giorgetti, L., Fudenberg, G., & Nora, E. P. (2025) · doi:10.1101/2025.08.14.667581 · Cited by 15 · see citing works
Hirano, T. (2025) · The Journal of Cell Biology · doi:10.1083/jcb.202504075 · Cited by 12 · see citing works
Two CTCF motifs impede cohesin-mediated DNA loop extrusion
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Self-citationChromatin insulators in gene regulation and 3D genome organization
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De novo formation of cis-regulatory contacts in the absence of NIPBL-driven chromatin loop extrusion
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PDS5 proteins control genome architecture by limiting the lifetime of cohesin-NIPBL complexes.
Wutz, G., Davidson, I., Banigan, E., Stocsits, R. R., Kawasumi, R., Tang, W., Nagasaka, K., Costantino, L., Jansen, R.-P., Hirota, K., et al. (2026) · Molecules and Cells · doi:10.1016/j.molcel.2026.03.025 · Cited by 6 · see citing works
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Physiological aging in three dimensions
Ma, F., & Sen, R. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.08.002 · Cited by 10 · see citing works
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NIPBL and STAG1 enable loop extrusion by providing differential DNA–cohesin affinity
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Self-citationLoop extrusion creates rare, long-lived encounters underlying enhancer-promoter communicationPreprint
Ubertini, M. A., Louafi, N., Landry, K., Kos, P. I., Roth, G., Marchi, E., Cramard, J., Tiana, G., & Giorgetti, L. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.24.678119 · Cited by 8 · see citing works
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Liquid condensates: a new barrier to loop extrusion?
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Molecular determinants of Smc5/6 association with DNA junctions
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The establishment of the 3D genome structure during zygotic genome activation
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DNA actively regulates the “safety-belt” dynamics of condensin during loop extrusion
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Chromatin folding principles underlying the generation of antibody diversity
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Theory of chromosome structural dynamics by processive loop extrusion.
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Wang, S., Zhang, X., Jia, T., Wang, W., Liu, X., Lin, H., Pan, H., Zhang, J., Li, D., Zhang, L., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02688-7 · Cited by 2 · see citing works
Nurislamov, A. R., & Yunusova, A. (2025) · Cells · doi:10.3390/cells15010051 · Cited by 2 · see citing works
A splicing factor-cohesin association links RNA processing to cohesin-dependent genome folding
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Cohesin extrudes chromatin loop unidirectionally through two modes of mechanisms in human cellsPreprint
Wang, P., Meng, L., Jiang, L., Li, Y., Huang, J., Tiancheng, Y. U., Chai, H., Kim, M., Wang, X., & Ruan, Y. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.01.722300 · Cited by 1 · see citing works
Kochanova, N. Y., Vermeren, M., Prevo, B., Ustun, I., Webb, S., Xie, L., Earnshaw, W. C., & Paulson, J. R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.16.665228
MIA-Jet: Multi-scale Identification Algorithm of Chromatin JetsPreprint
Kim, S., & Kim, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.27.672730
A tale of two forms of cohesin in DNA repair
Hu, J. (2025) · Science · doi:10.1126/science.aed1859
SMC Motor Proteins Operate at the Near-Minimal Forces for DNA Loop ExtrusionPreprint
Pinto, A., Pradhan, B., Tetiker, D., Schmitt, M. P., Kim, E., & Virnau, P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.05.709531
Structural and mechanistic perspectives on Nse5/6 regulation of the Smc5/6 complex
Kim, J. H., Rao, D. R., & Kim, K.-D. (2026) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2026.1757821
Chromosome segregation in a minimal bacterial cell driven by SMC protein complexes
Maytin, A. K., Gilbert, B. R., & Luthey-Schulten, Z. (2026) · Protein Science · doi:10.1002/pro.70604
DNA-folding changes block production of self-directed antibodies
Gao, Z., & Boyes, J. (2026) · Nature · doi:10.1038/d41586-026-01329-7
Alkurdi, B., Hernandez, J., Lewis, A. H., Snyder, L. M., Markus, S., & Swygert, S. G. (2026) · bioRxiv · doi:10.64898/2026.07.10.737861
Smc5/6 uses its head-NSE module to preferentially associate with ssDNA gaps and ss-dsDNA junctions
Irvin, E. M., Park, S. T., Miller-Browne, V., Lever, R., Li, S., Waterman, G., Kaur, P., Zhao, X., & Wang, H. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag624
Structural Maintenance of Chromosomes Complexes in Bacteria
Sanath-Kumar, R., Liao, Q., Ren, Z., & Wang, X. (2026) · Annual Review of Microbiology · doi:10.1146/annurev-micro-041222-034556
Mechanisms and functional implications of long-range enhancer-dependent gene regulation
Iliadou, M., Haro, E., & Rada-Iglesias, Á. (2026) · Nature Genetics · doi:10.1038/s41588-026-02721-9
What Is the Role of Cohesin in Transcription Regulation?
Ulianov, S. V., & Razin, S. V. (2026) · Biochemistry (Moscow) · doi:10.1134/s0006297926602285
Transcription-coupled recruitment of SMC complexes in yeast
Kim, J., Chae, Y.-S., & Kim, K.-D. (2026) · FEMS Yeast Research · doi:10.1093/femsyr/foag056
- Authors
- Barth, R., Davidson, I. F., van der Torre, J., Taschner, M., Gruber, S., Peters, J.-M., & Dekker, C.
- Affiliations
- Delft University of Technology (NL)
- Research Institute of Molecular Pathology (AT)
- University of Lausanne (CH)
- Corresponding author
- Dekker, Cees
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2025-02
- Volume
- 188
- Issue
- 3
- Pages
- 749-763.e21
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W4406464901
- Cited by
- 40
- References
- 80
- Citations by year
- 2026: 22 · 2025: 18
- FWCI
- 12.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- IRIS (submittedVersion, cc-by-nc)
- SERVAL (Université de Lausanne) (submittedVersion, cc-by-nc)
- Funders
- Human Frontier Science Program (RGP0057/2018)
- Österreichische Forschungsförderungsgesellschaft (FFG-FO999902549)
- Vienna Science and Technology Fund (LS19-029)
- European Research Council
- Medizinische Universität Wien
- HORIZON EUROPE European Research Council (101020558, 883684, 724482)
- Boehringer Ingelheim
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Keywords
- DNA loop extrusion, cohesin, genome organization, single-molecule DNA mechanics
- MeSH terms
- Cohesins, Chromosomal Proteins, Non-Histone, DNA, Saccharomyces cerevisiae, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins
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