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Self-organization of domain structures by DNA-loop-extruding enzymes.

Alipour E, Marko JF - Nucleic Acids Res. (2012)

Bottom Line: If these machines do not dissociate from DNA (infinite processivity), a disordered, exponential steady-state distribution of small loops is obtained.The size of the resulting domain can be simply regulated by boundary elements, which halt the progress of the extrusion machines.This mechanism could explain the geometrically uniform folding of eukaryote mitotic chromosomes, through extrusion of pre-programmed loops and concomitant chromosome compaction.

View Article: PubMed Central - PubMed

Affiliation: Center for Cell Analysis and Modeling, University of Connecticut Health Sciences Center, Farmington, CT 06030, USA. elnaz.alipour@gmail.com

ABSTRACT
The long chromosomal DNAs of cells are organized into loop domains much larger in size than individual DNA-binding enzymes, presenting the question of how formation of such structures is controlled. We present a model for generation of defined chromosomal loops, based on molecular machines consisting of two coupled and oppositely directed motile elements which extrude loops from the double helix along which they translocate, while excluding one another sterically. If these machines do not dissociate from DNA (infinite processivity), a disordered, exponential steady-state distribution of small loops is obtained. However, if dissociation and rebinding of the machines occurs at a finite rate (finite processivity), the steady state qualitatively changes to a highly ordered 'stacked' configuration with suppressed fluctuations, organizing a single large, stable loop domain anchored by several machines. The size of the resulting domain can be simply regulated by boundary elements, which halt the progress of the extrusion machines. Possible realizations of these types of molecular machines are discussed, with a major focus on structural maintenance of chromosome complexes and also with discussion of type I restriction enzymes. This mechanism could explain the geometrically uniform folding of eukaryote mitotic chromosomes, through extrusion of pre-programmed loops and concomitant chromosome compaction.

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Related in: MedlinePlus

Schematic drawing of machine positions on the lattice as time progresses; lattice model equivalent is sketched below each panel. Black dumbbell shapes (and arrows in the lattice sketch) depict enzymes and green lines show DNA. Panel (a) depicts the starting point and the progression of infinitely processive machines, while Panel (b) shows machines with lower processivity (disassociation rate is still relatively small, see text). Panel (c) depicts a single step, with ATP binding, hydrolysis and release associated with extrusion of a small amount of DNA.
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gks925-F1: Schematic drawing of machine positions on the lattice as time progresses; lattice model equivalent is sketched below each panel. Black dumbbell shapes (and arrows in the lattice sketch) depict enzymes and green lines show DNA. Panel (a) depicts the starting point and the progression of infinitely processive machines, while Panel (b) shows machines with lower processivity (disassociation rate is still relatively small, see text). Panel (c) depicts a single step, with ATP binding, hydrolysis and release associated with extrusion of a small amount of DNA.

Mentions: Here, we describe an active mechanism able to form specific and large loop domains of precise size, based on hypothetical DNA-loop-extruding enzyme machines with general properties consistent with those of condensins. We consider a DNA lattice of some finite length, on which M enzymes are bound; each enzyme is assumed to have two binding domains which can bind and therefore bridge two DNA sites (Figure 1). The size of the lattice sites is comparable to the persistence length of DNA (or chromatin), and also to the size of the machines, nm. When a machine binds to the DNA lattice, it associates with adjacent lattice sites, i.e. DNA sites separated by a distance comparable to the size of the enzyme. We suppose that ATP hydrolysis causes each binding domain (motile element) to move along the DNA, away from its partner; the protein link between the two motile elements leads the motility to drive extrusion of a DNA loop. The only interaction between the pairs considered in our model is their steric repulsion. Beyond this the only other ingredient is whether or not dissociation of the machines from DNA is permitted. In the absence of dissociation, a relatively disordered series of variable-size loops results (Figure 1a). However, when dissociation and re-association of the machines occur, they self-organize into a robustly ordered ‘stack’, anchoring a sturdy loop domain (Figure 1b).Figure 1.


Self-organization of domain structures by DNA-loop-extruding enzymes.

Alipour E, Marko JF - Nucleic Acids Res. (2012)

Schematic drawing of machine positions on the lattice as time progresses; lattice model equivalent is sketched below each panel. Black dumbbell shapes (and arrows in the lattice sketch) depict enzymes and green lines show DNA. Panel (a) depicts the starting point and the progression of infinitely processive machines, while Panel (b) shows machines with lower processivity (disassociation rate is still relatively small, see text). Panel (c) depicts a single step, with ATP binding, hydrolysis and release associated with extrusion of a small amount of DNA.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526278&req=5

gks925-F1: Schematic drawing of machine positions on the lattice as time progresses; lattice model equivalent is sketched below each panel. Black dumbbell shapes (and arrows in the lattice sketch) depict enzymes and green lines show DNA. Panel (a) depicts the starting point and the progression of infinitely processive machines, while Panel (b) shows machines with lower processivity (disassociation rate is still relatively small, see text). Panel (c) depicts a single step, with ATP binding, hydrolysis and release associated with extrusion of a small amount of DNA.
Mentions: Here, we describe an active mechanism able to form specific and large loop domains of precise size, based on hypothetical DNA-loop-extruding enzyme machines with general properties consistent with those of condensins. We consider a DNA lattice of some finite length, on which M enzymes are bound; each enzyme is assumed to have two binding domains which can bind and therefore bridge two DNA sites (Figure 1). The size of the lattice sites is comparable to the persistence length of DNA (or chromatin), and also to the size of the machines, nm. When a machine binds to the DNA lattice, it associates with adjacent lattice sites, i.e. DNA sites separated by a distance comparable to the size of the enzyme. We suppose that ATP hydrolysis causes each binding domain (motile element) to move along the DNA, away from its partner; the protein link between the two motile elements leads the motility to drive extrusion of a DNA loop. The only interaction between the pairs considered in our model is their steric repulsion. Beyond this the only other ingredient is whether or not dissociation of the machines from DNA is permitted. In the absence of dissociation, a relatively disordered series of variable-size loops results (Figure 1a). However, when dissociation and re-association of the machines occur, they self-organize into a robustly ordered ‘stack’, anchoring a sturdy loop domain (Figure 1b).Figure 1.

Bottom Line: If these machines do not dissociate from DNA (infinite processivity), a disordered, exponential steady-state distribution of small loops is obtained.The size of the resulting domain can be simply regulated by boundary elements, which halt the progress of the extrusion machines.This mechanism could explain the geometrically uniform folding of eukaryote mitotic chromosomes, through extrusion of pre-programmed loops and concomitant chromosome compaction.

View Article: PubMed Central - PubMed

Affiliation: Center for Cell Analysis and Modeling, University of Connecticut Health Sciences Center, Farmington, CT 06030, USA. elnaz.alipour@gmail.com

ABSTRACT
The long chromosomal DNAs of cells are organized into loop domains much larger in size than individual DNA-binding enzymes, presenting the question of how formation of such structures is controlled. We present a model for generation of defined chromosomal loops, based on molecular machines consisting of two coupled and oppositely directed motile elements which extrude loops from the double helix along which they translocate, while excluding one another sterically. If these machines do not dissociate from DNA (infinite processivity), a disordered, exponential steady-state distribution of small loops is obtained. However, if dissociation and rebinding of the machines occurs at a finite rate (finite processivity), the steady state qualitatively changes to a highly ordered 'stacked' configuration with suppressed fluctuations, organizing a single large, stable loop domain anchored by several machines. The size of the resulting domain can be simply regulated by boundary elements, which halt the progress of the extrusion machines. Possible realizations of these types of molecular machines are discussed, with a major focus on structural maintenance of chromosome complexes and also with discussion of type I restriction enzymes. This mechanism could explain the geometrically uniform folding of eukaryote mitotic chromosomes, through extrusion of pre-programmed loops and concomitant chromosome compaction.

Show MeSH
Related in: MedlinePlus