6 Биосинтез нуклеиновых кислот (1160075)
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Лекция 6.Биосинтез нуклеиновых кислот/799Figure 23—9 Supercoils. A typical phone cord is acoil. A phone cord twisted as shown is a supercoil.The illustration is especially appropriate, becausean examination of the twisting of phone cordshelped lead Jerome Vinograd and colleagues tothe insight that many properties of small, circularDNAs could be explained by supercoiling.
They firstdetected DNA supercoiling in small, circular viralDNAs in 1965.Coil —<&*-> i?As can be seen in Figure 23-8, the introns of this particular gene aremuch longer than the exons; altogether the introns make up 85% of theDNA of this gene.
Most eukaryotic genes examined thus far appear tocontain introns that vary in number, position, and the fraction of thetotal length of the gene they occupy. For example, the serum albumingene contains 6 introns, the gene for the protein conalbumin of thechicken egg contains 17 introns, and a collagen gene has been found tohave over 50 introns. Genes for histones provide an example of a familyof genes that appear to have no introns.
Only a few prokaryotic genescontain introns. In most cases the function of introns is not clear.DNA SupercoilingFrom the examples given above, it is clear that cellular DNA must bevery tightly compacted just to fit into the cell. This implies a highdegree of structural organization.
It is not enough just to fold the DNAinto a small space, however. The packaging must permit access to theinformation in the DNA for processes such as replication and transcription. Before considering how this is accomplished, we must examine an important property of DNA structure that we have not yet considered—DNA supercoiling.The term "supercoiling" means literally the coiling of a coil. A telephone cord for example, is typically a coiled wire.
The twisted pathoften taken by that wire as it goes from the base of the phone to thereceiver generally describes a supercoil (Fig. 23-9). DNA is coiled inthe form of a double helix. Let us define an axis about which bothstrands of the DNA coil. A bending or twisting of that axis upon itself(Fig. 23-10) is referred to as DNA supercoiling. As detailed below,DNA supercoiling is generally a manifestation of structural strain.Conversely, if there is no net bending of the DNA axis upon itself, theDNA is said to be in a relaxed state.It is probably apparent that DNA compaction must involve someform of supercoiling. Perhaps less apparent is the fact that replicatingor transcribing DNA also must induce some degree of supercoiling.Figure 23-10 Supercoiling of DNA.
Supercoiling isthe twisting of the DNA axis upon itself.khv*«—Supercoil/AxisDNA double helix(coil)AxisDNA supercoil800Part IV Information PathwaysFigure 23-11 Supercoiling induced by separatingthe strands of a helical structure. Twist two linearstrands of rubber band into a right-handed doublehelix as shown. Fix the left end by having a friendhold onto it. If the two strands are pulled apart atthe right end, the resulting strain will produce supercoiling as shown.Replication and transcription both require a transient separation ofthe strands of DNA, and this is not a simple process in a DNA structure in which the two strands are helically interwound. Figure 23-11illustrates this point.That supercoiling must occur in cellular DNA would seem almosttrivial were it not for one additional fact: many circular DNA moleculesremain highly supercoiled even after they are purified from proteinand other cellular components.
Supercoiling is an important and intrinsic aspect of DNA tertiary structure that is ubiquitous in cellularDNAs and highly regulated by each cell.A number of quantifiable properties of supercoiling have been established, the study of which has provided many insights into DNAstructure and function. This work has drawn heavily on concepts derived from a branch of mathematics called topology, the study of properties of an object that do not change under continuous deformations.In the case of DNA, a topological property is one that is not affected bytwisting and turning of the DNA axis and can only be changed bybreakage and rejoining of the DNA backbone. We now turn to an examination of the fundamental properties of supercoiling and the physicalorigin of the phenomenon itself.Most Cellular DNA Is UnderwoundFigure 23-12 Electron micrographs of relaxed andsupercoiled plasmid DNAs.
The molecule at the leftis relaxed, and the degree of supercoiling increasesfrom left to right.To understand supercoiling we must now focus on the properties ofsmall, circular DNAs such as plasmids and the DNAs derived frommany small DNA viruses. When these DNAs contain no breaks in either strand, they are called closed-circular DNAs. If the DNA making up a closed-circular molecule conforms closely to the B-form structure (see Fig. 12-15), with one turn of the double helix for each 10.5base pairs, the DNA will be relaxed rather than supercoiled (Fig.23-12).
Supercoiling is not a random process and does not occur unlessthe DNA is subject to some form of structural strain. When purified,however, closed-circular DNAs are rarely relaxed regardless of theirbiological origin. Furthermore, the degree of supercoiling tends to bewell defined and characteristic of DNAs derived from a given cellularsource. These facts suggest that the DNA structure is strained in someway to induce the supercoiling, and that the degree of strain introduced is regulated by the cell.0 2/urnChapter 23 Genes and ChromosomesIn almost every instance, the strain is a result of an underwinding of the DNA in the closed circle.
In other words, there are fewerhelical turns in the DNA than would be expected for the B-form structure. The effect of underwinding is illustrated in Figure 23-13 for an84 base pair segment of a circular DNA. If the DNA were relaxed, thissegment would contain eight double-helical turns, or one for every 10.5base pairs. If one of these turns is removed, there will be 84/7 or about12.0 base pairs per turn rather than the 10.5 found in B-DNA. This is adeviation from the most stable DNA form, and the molecule is thermodynamically strained as a result.
The strain can be accommodated inone of two ways. First, the two strands can simply separate over thedistance corresponding to one turn of B-DNA—10.5 base pairs (Fig.23-13). Alternatively, the DNA can form a supercoil. When the axis ofthe DNA is twisted on itself in a certain manner, neighboring basepairs in underwound DNA can stack in positions that more closelyapproximate those they would assume in B-DNA.Every cell actively underwinds its DNA with the aid of enzymaticprocesses to be described below. The resulting strained state of theDNA represents a form of stored energy.
In isolated closed-circularDNA, strain introduced by underwinding generally is accommodatedby supercoiling rather than strand separation, because twisting theaxis of the DNA usually requires less energy than breaking the hydrogen bonds that stabilize paired bases. As we shall see below, however,the underwinding of DNA in vivo makes it easier to separate DNAstrands and thereby gain access to the information they contain. Facilitating strand separation is one important reason for maintainingDNA in an underwound state.The underwound state can be maintained only if the DNA is aclosed circle or if it is bound and stabilized by proteins such that thestrands are not free to rotate about each other.
If there is a break inone of the strands of a protein-free circular DNA, free rotation at thatpoint will cause the underwound DNA to revert spontaneously to therelaxed state. In a closed-circular DNA, however, the number of helicalturns present is fixed and cannot be changed without at least transiently breaking one of the DNA strands.
The number of helical turnsin DNA is quantifiable and leads to a more precise description of supercoiling.DNA Underwinding Is Defined by Topological LinkingNumberThe branch of mathematics called topology provides a number of ideasthat are useful in this discussion. Perhaps foremost among these is theconcept of linking number.
The linking number of a DNA moleculerigorously specifies the number of helical turns in a closed-circularDNA, in the absence of any supercoiling. Linking number is a topological property because it does not vary when double-stranded DNA istwisted or deformed in any way, as long as both DNA strands remainintact.The concept of linking number (Lk) is illustrated in Figure 23-14.We begin by separating the two strands of a double-stranded circularDNA. If these two strands are linked as shown in Figure 23-14a, theyare effectively joined by what can be described as a topological bond.801Relaxed (8 turns)(a)Strained (7 turns)(b)Strand separation(c)Supercoil(d)Figure 23-13 The effects of DNA underwinding.(a) A segment of DNA, 84 base pairs long, in itsrelaxed form with eight helical turns, (b) Removalof one turn induces structural strain that can beaccommodated by (c) strand separation over 10.5base pairs or by (d) formation of a supercoil.Lk=6(b)Lk =(a)Figure 23—14 Linking number, Lk.
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