DNA supercoiling is an expression of the strain on a DNA strand and refers to the over- or under-winding of that strand. When the double helix in three-dimensional space is twisted around its own axis, supercoiling occurs in the DNA molecules.
Inside cells, DNA molecules are generally negatively supercoiled, albeit the quantity of supercoiling varies across the genome and many supercoils may be limited by binding proteins. Supercoiling boosts DNA’s free energy and regulates DNA metabolism by boosting or inhibiting particular enzyme activities.
The principal enzymes that govern DNA topology are DNA topoisomerases, and numerous distinct kinds of enzymes are found in all cells.
Double-stranded DNA helices may wind in three-dimensional space to produce higher-order helices, resulting in supercoiled DNA. The extent of supercoiling in a DNA molecule is influenced by environmental conditions, such as ionic strength and temperature; since supercoiling of DNA influences, the biological pathways in which it is involved, the level of DNA supercoiling inside cells is tightly regulated.
Supercoiling provides a significant amount of free energy to DNA molecules and, inside cells, this can be used to drive structural transitions and other metabolic processes that would normally be thermodynamically unfavorable, such as the opening of the DNA helix during replication and transcription.
Mathematical and modeling studies have provided insight for quantitative analyses of DNA supercoiling, leading to definitions for a twist, which describes how the individual strands of DNA coil around its axis, and writhe, which describes how the helix axis coils in three‐dimensional space.
DNA inside cells contains supercoils of two types: interwound supercoiling occurs when circular DNA winds around its own axis and toroidal supercoiling occurs when the DNA helix forms a series of spirals around an imaginary ring.
A wide variety of proteins that bind to DNA alter the local geometry of its helix and influence DNA topology; an important characterized example of this effect is the winding of DNA around the eukaryotic histone octamer to form the nucleosome.
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A fundamental feature of closed domains of DNA, such as a circular molecule, is that the two strands of DNA are topologically linked and strand separation can be achieved only by breakage of one of the strands; the main enzymes that regulate DNA topology are DNA topoisomerases and they usually act to remove or introduce negative supercoils or they may remove both positive and negative supercoils.
Cellular processes that move macromolecular assemblies along DNA may generate localized DNA supercoiling since as the large protein complex moves along the DNA, its rotation around the DNA may be inhibited.
CHANGES FROM ONE FORM TO ANOTHER OF DNA
Local structural transitions from the common B-DNA conformation into other DNA forms can be functionally important. The formation of non-B-DNA within certain sequence elements of DNA can be induced by changes in environmental conditions, protein binding, and superhelical tension. Several lines of evidence indicate that alternative DNA structures exist in prokaryotic and eukaryotic cells.
The data on their involvement in replication, gene expression, recombination, and mutagenesis continues to accumulate. Genetic information is generally stored in long double-stranded DNA molecules. Hydrogen bonding between nucleobases keeps the complementary DNA strands organized into a right-handed helical structure called B-DNA.
Several non-B-DNA structures (oftentimes called unusual or alternative DNA structures) can be important for interactions with proteins involved in replication, gene expression, and recombination. They may also play different roles in the formation of nucleosomes and other supramolecular structures involving DNA. DNA sequences characterized as “random” or “mixed sequence” typically only form A-DNA or B-DNA.
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Special sequence characteristics or defined symmetry elements are required to form alternative structures such as left-handed Z-DNA, cruciforms, intramolecular triplexes, quadruplex DNA, slipped strand DNA, parallel-stranded DNA, and unpaired DNA structures.
Together with variations in DNA supercoiling, local alternative structures provide enormous potential for autoregulation of DNA functions.Structural transitions into other DNA forms can occur within certain sequence elements of DNA and these can be functionally important.
Several non-B-DNA structures (oftentimes called unusual or alternative DNA structures) can be important for interactions with proteins involved in replication, gene expression, and recombination. They may also play different roles in the formation of nucleosomes and other supramolecular structures involving DNA.
DNA sequences characterized as “random” or “mixed sequence” typically only form A-DNA or B-DNA. Special sequence characteristics or defined symmetry elements are required to form alternative structures such as left-handed Z-DNA, cruciforms, intramolecular triplexes, quadruplex DNA, slipped strand DNA, parallel-stranded DNA, and unpaired DNA structures.
Together with variations in DNA supercoiling, local alternative structures provide enormous potential for autoregulation of DNA functions.
ENZYMES INVOLVED IN DNA SUPERCOILING
Topoisomerases are enzymes that are responsible for the introduction and elimination of supercoils. Positive and negative supercoils require two different topoisomerases. This prevents the distortion of DNA by the specificity of the topoisomerases.
The two classes of topoisomerases are Type I and Type II. Type I stimulates the relaxation of supercoiled DNA and Type II uses the energy from ATP hydrolysis to add negative supercoils to DNA. Both of these classes of topoisomerases have important roles in DNA transcription, DNA replication, and recombinant DNA.
Topoisomerase forms loops (unwinded regions of the double helix) of negative supercoils. If the DNA lacks superhelical tension, there is no unwinding of supercoils.
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Type I topoisomerase
Type I topoisomerase acts by creating transient single-strand breaks in DNA. Topoisomerase I is a ubiquitous enzyme whose function in vivo is to relieve the torsional strain in DNA, specifically to remove positive supercoils generated in front of the replication fork and to relieve negative supercoils occurring downstream of RNA polymerase during transcription.
Topoisomerase I does not require ATP for catalytic activity. It binds double-strand DNA over 15–25 bp (with a preference for supercoiled or bent DNA) followed by cleavage of one DNA strand and forming a transient covalent phosphotyrosyl bond at the 3′-end of DNA. DNA torsional strain is then relieved by a “controlled rotation” mechanism subsequent to which the cleaved DNA is relegated.
The three-dimensional crystal structure of human topoisomerase I, both in covalent and noncovalent complexes with DNA, has defined the structural elements of the enzyme that contacts DNA. The association between topoisomerase I and the 3′-end of cleaved DNA has been termed the cleavable complex, which is stabilized by topoisomerase I inhibitors. This is further classified as type IA and types IB.
Type IA topoisomerases
Type IA topoisomerases enzyme is a 695-residue monomer and it relaxes negatively supercoiled DNA. First, Type IA cuts single-stranded DNA and catenates two circles of single-stranded DNA. Then it unwinds the supercoiled duplex DNA in one turn. Type IA has a specific strand-passage mechanism
which is the denaturation of type IA incubated with single-stranded DNA that yields linear DNA by phospho-Tyr diester linkage.
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Type IB topoisomerases
Type IB mediates a controlled rotation mechanism to relax both negative and positive supercoils. Type IB cleaves a single strand of a duplex DNA through the nucleophilic attack of an active site with Tyr on a DNA to yield a 3′-linked phospho-Tyr intermediate with a 5′-OH group.
Type IB consists of several domains and subdomains. Interestingly, type IA topoisomerases form a covalent intermediate with the 5′ end of DNA, while the IB topoisomerases form a covalent intermediate with the 3′ end of DNA.
Type II topoisomerase
Type II topoisomerase is an enzyme that requires ATP hydrolysis to complete a reaction cycle in which two DNA strands are cleaved, duplex DNA is passed through the break and the break is resealed. Type II cuts both strands a DNA double helix passes another unbroken DNA strand through it and then reanneals the cut strand.
Topo II enzymes have the ability to cut both strands of a double-stranded DNA molecule, pass another portion of the duplex through the cut, and reseal the cut in a process that utilizes ATP. All type II topoisomerases catalyze catenation and decatenation, that is, the linking and unlinking, of two different DNA duplexes
It is also split into two subclasses: type IIA and type IIB topoisomerases, which share similar structures and mechanisms.
Examples of type IIA topoisomerases include eukaryotic topo II, E. coli gyrase, and E. coli topo IV. Examples of type IIB topoisomerase include topo VI.
Supercoiling requires energy because it is torsionally strained. Thus, through the coupling to ATP hydrolysis, it can introduce negative supercoils.
In bacteria, Type II topoisomerase is also known as DNA gyrase. Gyrase is an enzyme that acts similarly to human Type II topoisomerase. Antibiotics act on bacterial enzymes by blocking the binding of ATP to gyrase and thus deactivating the breaking and joining of bacterial DNA chains.
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CONCEPT OF LINKING NUMBERS
The linking number is a topological property of DNA. A linking number is a sum of twists and writhes. The number of times one strand of DNA turned around another strand is called a twist while inter-coiling of the double helix is termed as writhe.
In short, writhe is a number of a time DNA double helix is crossed, coiled over each other, or the number of times one strand wraps around another strand.
As per the Watson and Cricks model, eukaryotic DNA is right-handed and negatively supercoiled DNA writhe is more important, as it will help in the arrangement of DNA. Here writhe can be interwound or overwound. Interwound writhe is plectonemic which means it wraps around each other or over the axis.
While over-wound writhe is spiral. The classic example of spiral winding is histone and DNA assembly, dsDNA is wrapped around histone in a spiral manner during nucleosome formation.
DNA Linking Number
The sum of the total number of twists and writhes is called a linking number. If both ends of DNA are joined, the linking number remains unchanged, (the linking number is zero in the case of a circular DNA molecule). So if we want to change the linking number, we have to break the DNA strand and that function is performed by DNA topoisomerase.
Importantly, twist and writhe can be interconvertible, in cccDNA under some distortion conditions some of the twists can be converted into writhe and some of the writhes can be converted into the twist. However, the total of both remains the same (because, Lk= Tw + Wr).
Eukaryotic DNA is B form, right-handed and under-wound which means it is negatively supercoiled. Left-handed DNA is positively supercoiled and overwound.
In DNA supercoiling, writhe is also dependent on the twist. As we know the writhe is dependent on the axial stress of DNA, when the number of twist increase, it increases the torsional tension on the axis of DNA, and ultimately the writhe will increase. This change makes DNA supercoiled and packed even tighter on the chromosome.
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In cccDNA, writhes remain zero as there is no inter-coiling between dsDNA observed. here, if,
Lk= Tw + Wr
For cccDNA (writhe is equal to zero)
So, Lk= Tw.
If cccDNA is fully relaxed which means it does not have any supercoiling, in this condition the linking number becomes zero hence supercoiling in cccDNA is denoted as Lk0.
As per the Watson and Crick model, the dsDNA has 10.5 bp per helix and is relaxed. The relaxed cccDNA has a total of 1050 bp so the total linking number is,
Linking number (Lk)= total number of base/basepair per helical turn
hence, Lk= 1050 bp / 10.5 (bp/turn)
Lk= +1000 (because the DNA is other than B form and left-handed)
It is indicated that if our DNA is left-handed and has 10.5 bp per turn with 1050 bp length then one strand is cross or over-wound (positive supercoiling) to another strand 1000 times.
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