Loop extrusion

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Depiction of the loop extrusion process where a loop extruder lands (top), extrudes a loop (middle), and unbinds (bottom). Loop extrusion.svg
Depiction of the loop extrusion process where a loop extruder lands (top), extrudes a loop (middle), and unbinds (bottom).

Loop extrusion is a major mechanism of Nuclear organization. It is a dynamic process in which structural maintenance of chromosomes (SMC) protein complexes progressively grow loops of DNA or chromatin. In this process, SMC complexes, such as condensin or cohesin, bind to DNA/chromatin, use ATP-driven motor activity to reel in DNA, and as a result, extrude the collected DNA as a loop.

Contents

Background

The organization of DNA presents a remarkable biological challenge: human DNA can reach 2 meters [1] and is packed into the nucleus with the diameter of 5-20 µm. [2] At the same time, the critical cell processes involve complex processes on highly compacted DNA, such as transcription, replication, recombination, DNA repair, and cell division.

Loop extrusion is a key mechanism that organizes DNA into loops, enabling its efficient compaction and functional organization. For instance, in vitro experiments show that cohesin can compact DNA by 80%, [3] while condensin achieves a remarkable 10,000-fold compaction of mitotic chromosomes, as evidenced by microscopy, Hi-C, and polymer simulations. [4]

Another challenge lies in establishing long-range genomic communication, which can span hundreds of thousands of base pairs. [5] Physical encounters between genomic elements are intrinsically random and promiscuous without mechanisms to facilitate them. [6] Loop extrusion has been proposed to provide an effective solution to regulate contacts by bringing target elements into proximity while limiting contact with unwanted loci. [7]

Key components of the loop extrusion process Loop extrusion components2.svg
Key components of the loop extrusion process

Key components

The key components of the loop extrusion process are

SMC proteins

Loop extrusion is performed by the SMC family of protein-complexes which includes cohesin, condensin, and SMC5/6 [9] each playing specialized roles depending on the organism, cell cycle phase, and biological context. Cohesin mediates chromatin loop formation and stabilization, particularly during interphase in vertebrates, where it facilitates transcriptional regulation by promoting distal enhancer-promoter interactions. During mitosis and meiosis, cohesin dissociates from chromosome arms ceding its loop extrusion role to condensin. Loop extrusion by condensin mediates large-scale chromosome compaction, creating the compact, rod-like chromosome structures required for accurate segregation. Unlike cohesin and condensin, SMC5/6 is a loop extruding factor which primarily functions in maintaining genome integrity during DNA damage repair and resolving replication stress. [9]

Despite their distinct roles, SMC complexes share a highly conserved ring-like structure. Two SMC proteins (usually, SMC1 and SMC3) are connected via a hinge region and linked at their heads by a kleisin subunit, forming a closed ring. These two SMC proteins have ATPase domains at their heads, which bind together and hydrolyze ATP. Cycles of ATP binding and hydrolysis mediate conformational changes in the ring structure, driving DNA translocation and stepwise loop extrusion. ATP is essential for both initiating loop extrusion (e.g., loading SMC complexes onto DNA) and propagating it (growing loops by translocating along DNA). The tension within the DNA significantly influences extrusion efficiency. At low tension, SMC complexes can make larger loop-capture steps, while higher tension can lead to stalling or reversal of loop extrusion. [10] [11]

Modifications and factors for loading/unloading

The dynamic nature of loop extrusion is tightly controlled by accessory factors and post-translational modifications, especially in the case of cohesin. In vertebrates, NIPBL (and orthologs like Mau2 in yeast or SCC2 and SCC4) is crucial for loading SMC complexes onto DNA, initiating and maintaining active extrusion. PDS5 is thought to pause the extrusion process. The SMC can then either restart extruding or be unloaded by the additional binding of WAPL, which ensure proper recycling and turnover. Post-translational modifications also play a key role. Acetylation of cohesin by enzymes such as ESCO1 and ESCO2 stabilizes chromatin loops, particularly at CTCF-bound sites. Similarly, SUMOylation, mediated by the NSE2 subunit of the SMC5/6 complex, enhances the recruitment of SMC5/6 to sites of DNA damage, supporting its role in genomic stability.

Roadblocks of loop extrusion

Loop extruders can encounter various obstacles while extruding. For example, many of which were shown to directly interact with cohesin and hypothesized to stop its movement on DNA. However, in vivo experiments demonstrate that cohesin can frequently bypass obstacles larger than its ring size. [12]

  1. Other cohesin and condensin molecules: Extruding cohesins and condensins has been found to be obstacle to other extruders that they encounter on the way. [13] [4] As such, they present a fundamental road-block that can be randomly encountered on the DNA.
  2. CTCF: The C-terminal DNA-binding domain of CTCF has been shown to directly interact with SA2 and SCC1 subunits of cohesin to stop extrusion and retain it on DNA [14] with recent evidence suggesting a tension-dependence to the interaction. [15] CTCF stalls cohesin in a highly directional manner where cohesin can bypass CTCF in one orientation but stalls when encountering it in the opposite orientation. [16] This directionality allows for the creation of isolated domains on the genome called Topologically Associating Domains (TADs) which have been proposed to have a large role in gene-regulation. [17]
  3. Polymerase : Transcribing polymerases can serve as barriers to cohesin that may not only stall extruders but also act as a motor pushing cohesin in the direction of polymerase movement. [18] [19] The size of a polymerase with an RNA transcript is usually larger than the size of the cohesin ring, and the stall force of cohesin is much smaller than that of polymerase, [20] allowing for effective barrier function by polymerase. Furthermore, it has been found that RNA can directly interact with cohesin subunits. [21]
  4. Helicase : MCM helicase has been found to counteract the extrusion of cohesin on DNA. [22]
  5. R-loops: Some evidence suggests that R-loops can also act as barriers to loop extrusion, [23] and R-loops have been shown to interact with cohesin subunits. [21] However, other evidence suggests that R-loops may instead act as cohesin loaders. [24]

Molecular mechanism

The molecular mechanisms of DNA-loop extrusion by SMC proteins have not yet been fully understood, but recent structural studies have made significant progress in developing several working models, like the scrunching model, [25] the Brownian-ratchet model, the DNA-segment capture model/DNA-pumping model, the hold-and-feed model and the swing-and-clamp model. [26]

Evidence for loop extrusion

Evidence for loop extruding molecules and their properties

The first direct evidence of loop extrusion came from in vitro imaging studies on fluorescently labeled DNA with condensin [27] or cohesin. [3] [28] Extrusion was found to be ATP-dependent and happened at ~1-3kb/s. The stall force was measured to be around 0.1-1pN [29] [27] which is small compared to other molecular motors. [30]

Evidence for the biological role of loop extrusion

Most work on the biological role of loop extrusion relies on inhibiting loop extruders and observing the consequences. Depletion of cohesin leads to the disappearance of TADs and some loss in transcription genome-wide. [31] [32] In more specific settings, inhibition of cohesin has been found to inhibit neuronal maturation [33] and differentiation and function of dendritic cells. [34] Depletion of either condensin I or condensin II at the entry into mitosis leads to abnormal chromosome formation and improper segregation of sister chromatids. [4]

Biological function

Loop extrusion has been found across the tree of life with suggested roles in immune response, DNA repair, enhancer-promoter interactions, and mitosis.

Theoretical models of loop extrusion

In mathematical models of loop extrusion, the two legs of a loop-extruding factor (LEF) are represented as points on a one-dimensional line, evolving according to different extrusion policies:

Since the exact modalities of LEF dynamics remain uncertain, these models provide a flexible framework to explore different hypothetical behaviors of LEFs.

In these models, the statistics of LEFs are characterized by two key physical parameters: [13]

The interplay of these two parameters, encapsulated by the dimensionless parameter , defines two states of chromatin organization:

Related Research Articles

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.

<span class="mw-page-title-main">Condensin</span> Protein complex

Condensins are large protein complexes that play a central role in chromosome assembly and segregation during mitosis and meiosis. Their subunits were originally identified as major components of mitotic chromosomes assembled in Xenopus egg extracts.

SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.

An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.

<span class="mw-page-title-main">Cohesin</span> Protein complex that regulates the separation of sister chromatids during cell division

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.

<span class="mw-page-title-main">CTCF</span> Transcription factor

Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.

<span class="mw-page-title-main">NIPBL</span> Protein-coding gene in the species Homo sapiens

Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the NIPBL gene. NIPBL is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. Heterozygous mutations in NIPBL account for an estimated 60% of case of Cornelia de Lange Syndrome.

<span class="mw-page-title-main">SMC1A</span> Protein-coding gene in humans

Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

<span class="mw-page-title-main">Chromosome conformation capture</span> Method in molecular biology

Chromosome conformation capture techniques are a set of molecular biology methods used to analyze the spatial organization of chromatin in a cell. These methods quantify the number of interactions between genomic loci that are nearby in 3-D space, but may be separated by many nucleotides in the linear genome. Such interactions may result from biological functions, such as promoter-enhancer interactions, or from random polymer looping, where undirected physical motion of chromatin causes loci to collide. Interaction frequencies may be analyzed directly, or they may be converted to distances and used to reconstruct 3-D structures.

<span class="mw-page-title-main">RAD21</span> Protein-coding gene in humans

Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.

<span class="mw-page-title-main">SMC5</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 5 is a protein encoded by the SMC5 gene in human.

<span class="mw-page-title-main">NCAPH</span> Protein-coding gene in the species Homo sapiens

Condensin complex subunit 2 also known as chromosome-associated protein H (CAP-H) or non-SMC condensin I complex subunit H (NCAPH) is a protein that in humans is encoded by the NCAPH gene. CAP-H is a subunit of condensin I, a large protein complex involved in chromosome condensation. Abnormal expression of NCAPH may be linked to various types of carcinogenesis as a prognostic indicator.

<span class="mw-page-title-main">SMC2</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 2 (SMC-2), also known as chromosome-associated protein E (CAP-E), is a protein that in humans is encoded by the SMC2 gene. SMC2 is part of the SMC protein family and is a core subunit of condensin I and II, large protein complexes involved in chromosome condensation, overall organization. Several studies have demonstrated the necessity of SMC2 for cell division and proliferation.

Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.

<span class="mw-page-title-main">NCAPH2</span> Protein-coding gene in the species Homo sapiens

Condensin-2 complex subunit H2, also known as chromosome-associated protein H2 (CAP-H2) or non-SMC condensin II complex subunit H2 (NCAPH2), is a protein that in humans is encoded by the NCAPH2 gene. CAP-H2 is a subunit of condensin II, a large protein complex involved in chromosome condensation.

<span class="mw-page-title-main">SMC1B</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair. SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1B protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.

<span class="mw-page-title-main">Topologically associating domain</span> Self-interacting genomic region

A topologically associating domain (TAD) is a self-interacting genomic region, meaning that DNA sequences within a TAD physically interact with each other more frequently than with sequences outside the TAD. The average size of a topologically associating domain (TAD) is 1000 kb in humans, 880 kb in mouse cells, and 140 kb in fruit flies. Boundaries at both side of these domains are conserved between different mammalian cell types and even across species and are highly enriched with CCCTC-binding factor (CTCF) and cohesin. In addition, some types of genes appear near TAD boundaries more often than would be expected by chance.

<span class="mw-page-title-main">Nuclear organization</span> Spatial distribution of chromatin within a cell nucleus

Nuclear organization refers to the spatial organization and dynamics of chromatin within a cell nucleus during interphase. There are many different levels and scales of nuclear organisation.

<span class="mw-page-title-main">Insulated neighborhood</span>

In mammalian biology, insulated neighborhoods are chromosomal loop structures formed by the physical interaction of two DNA loci bound by the transcription factor CTCF and co-occupied by cohesin. Insulated neighborhoods are thought to be structural and functional units of gene control because their integrity is important for normal gene regulation. Current evidence suggests that these structures form the mechanistic underpinnings of higher-order chromosome structures, including topologically associating domains (TADs). Insulated neighborhoods are functionally important in understanding gene regulation in normal cells and dysregulated gene expression in disease.

In biology, the chromosome scaffold is the backbone that supports the structure of the chromosomes. It is composed of a group of non-histone proteins that are essential in the structure and maintenance of eukaryotic chromosomes throughout the cell cycle. These scaffold proteins are responsible for the condensation of chromatin during mitosis.

References

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