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Nucleic Acids Research Pages 1503-1508

Non-complementary DNA helical structure induced by positive torsional stress
Introduction
Materials And Methods
   Synthesis and purification of DNA
   Two-dimensional denaturing gel electrophoresis
   Non-denaturing polyacrylamide gel electrophoresis
   Visualization of topoisomers and the transition
Results
Discussion
Acknowledgements
References


Non-complementary DNA helical structure induced by positive torsional stress

Non-complementary DNA helical structure induced by positive torsional stress Alexander V. Vologodskii, Xiaoping Yang and Nadrian C. Seeman*

Department of Chemistry, New York University, New York, NY 10003, USA

Received October 27, 1997; Revised and Accepted January 22, 1998

ABSTRACT

We have induced a local conformational transition by positive torsional stress in small synthetic circular DNA molecules containing cruciforms with immobile or tetramobile branched junctions. The immobile species correspond to the extruded and intruded extrema of the tetramobile junction. Under normal conditions the sequences of all the branched species prevent them from being re-absorbed into the circle. We have induced positive stress by addition of ethidium to the circle, in a low ionic strength medium. Alterations in gel electrophoretic mobility under increasing concentrations of ethidium suggest that the cruciforms undergo a transition under torsional stress. The product of this transition contains mispaired nucleotides, but interwound backbones. By comparing the electrophoretic mobilities of circles containing these structures with that of a completely complementary circle of the same length, we conclude that the twist in the mispairing region is similiar to that of completely paired species.

INTRODUCTION

Since the discovery of cruciform formation in negatively supercoiled DNA (1-3) a great deal of effort has been devoted to the study of local conformational transitions in DNA secondary structure induced by the action of negative supercoiling. These transitions, formation of open regions, cruciform structures and the Z and H forms of DNA (reviewed in 4-9), usually occur at specific nucleotide sequences. Despite great diversity, the non-canonical structures share one common feature: interwinding of the complementary DNA strands is much lower in these structures than in canonical B-form DNA. Consequently, the formation of altered structures reduces the free energy of negative supercoiling. Indeed, negative torsional stress promotes formation of any structure that is underwound relative to B-form DNA. For the same reason positive torsional stress would promote formation of structures that are overwound relative to B-DNA. Such overwound structures are not known, however, and their occurrence is unlikely. Thus it would seem reasonable to believe that no local transitions in DNA can occur under the action of positive torsional stress.

The last statement suggests that the minimum energy state of torsionally relaxed DNA has all of its nucleotides paired in the regular B structure. Although this is usually true, exceptions are possible. For example, under specific solution conditions DNA segments with d(CG)n sequences adopt the Z conformation without any torsional stress (see reviews in 10,11); the action of positive torsional stress is likely to cause these segments to adopt the B conformation. A more interesting example is DNA molecules that contain stable cruciform structures derived from immobile or partially mobile 4-arm DNA branched junctions (12); these structures cannot be converted into regular linear double helices because the base pairs on the `extruded' arms lack complementarity (13). In theory, however, the cruciform structures could be destroyed if the positive torsional stress were large enough; this is true because the opposite strands could form interwound conformations, thereby reducing the torsional stress (Fig. 1a). From the Nucleic Acid Database (14) we only know of DNA structures containing a small number of contiguous mismatched nucleotides and detailed reports of their energetics are few (e.g. 15). Hence, it was not clear that the transition could be observed in practice. Nevertheless, under the action of positive torsional stress we have detected the transition of stable cruciforms into an interwound conformation containing non-complementary nucleotide pairs. Our analysis of this interwound conformation suggests that its overall twist is similar to the twist of DNA with perfect complementarity.a

Figure 1. Cruciform molecules and their transitions. (a) The transition described here. The structure on the left is a DNA minicircle containing a cruciform with an immobile (or partially mobile) branched junction whose opposite hairpin arms are not complementary to each other. The application of sufficient positive superhelical torsion by means of ethidium intercalation appears capable of inducing a conformational transition in the hairpin regions. The resulting structure appears to be an interwound conformation lacking in Watson-Crick complementarity, as indicated by the jagged segments. (b) The cruciform-containing molecular species used in this work. Three molecules containing a total of 298 nt in each strand are shown. At the lower left is the extruded immobile cruciform and at the lower right is the intruded immobile cruciform. Both of these molecules contain branch points fixed by sequence asymmetry. The differences are indicated by the 4 nucleotide pairs flanking the branch point. In the extruded immobile cruciform there are 262 nucleotide pairs in the circle to the base of the branch pont and 16 immobile pairs in the hairpins, which are capped by a dT4 loop in each strand. In the intruded immobile cruciform there are 270 nucleotide pairs in the circle and 12 immobile pairs in the hairpins. In the tetramobile cruciform shown at the top of the drawing the 4 nucleotide pairs that differentiate the two immobile cruciforms have been symmetrized, so that the molecule can undergo four steps of branch migration, as illustrated (13).

MATERIALS AND METHODS

Synthesis and purification of DNA

All DNA molecules in this study were synthesized on an Applied Biosystems 380B automatic DNA synthesizer, removed from the support and deprotected using standard phosphoramidite procedures (16). DNA strands have been purified by denaturing gel electrophoresis. Each of the final circular strands was synthesized from three different synthetic fragments, one of which contained the cruciform in its entirety. The portion of each strand containing the cruciform has been made in three different versions, to generate extruded immobile, intruded immobile and tetramobile cruciforms, as illustrated in Figure 1b; each strand contains 298 nt. The sequences of these strands and protocols for their phosphorylation, annealing and ligation have been published previously (13). A fourth strand was prepared complementary to strand 1 of the junction region (13), permitting assembly of a completely paired double-helical circle. In addition to a nominally relaxed circle, negatively supercoiled topoisomers of the completely paired circle were prepared by closing it in the presence of varying amounts of ethidium. These molecules were purified on two-dimensional denaturing gels. Nicked versions of each of these molecules were prepared by leaving one of the constituent strands unphosphorylated prior to ligation; nicked species were purified by non-denaturing gel electrophoresis.

Two-dimensional denaturing gel electrophoresis

All gels contained a ratio of 19:1 acrylamide:bisacrylamide, 7.0 M urea and a buffer consisting of 89 mM boric acid, 89 mM Tris, pH 8.3 (at 25°C), 2 mM Na2EDTA and 30-40% formamide. The sample was run on a 4% polyacrylamide gel. Each lane was then excised and run on a 7% denaturing polyacrylamide gel in a second dimension. Prior to loading onto gels the samples were dissolved in a denaturing loading dye containing 90% formamide and 5 mM EDTA and heated at 90°C for 3 min. Gels were run at 60°C at 31 V/cm.

Non-denaturing polyacrylamide gel electrophoresis

Gels contained 5% polyacrylamide (19:1 acrylamide:bisacrylamide) and a buffer consisting of 89 mM boric acid, 89 mM Tris, pH 8.3 (at 25°C), and 2 mM Na2EDTA. The sample buffer was the same, but contained 5% glycerol and 0.02% each of Bromophenol blue and Xylene cyanol FF tracking dyes. Gels were run on a Hoefer SE-200 gel electrophoresis unit at 20 V/cm for 3 h at 25°C, dried onto Whatman 3MM paper and exposed to X-ray film for up to 15 h; preparative gels were not dried.

Visualization of topoisomers and the transition

Radioactively labeled target molecules were first purified as a mixture of topoisomers using a two-dimensional (4 then 7%) polyacrylamide (19:1 acrylamide:bisacrylamide) denaturing gel. Topoisomers were then resolved on a 5% non-denaturing polyacrylamide gel (19:1 acrylamide:bisacrylamide) containing varied concentrations of ethidium bromide. Ethidium bromide was first added to the TBE running buffer and then introduced electrophoretically into the gel. These gels were run at room temperature. The constituents were then visualized by autoradiography, as described above.

RESULTS

Three different circular DNA molecules containing cruciforms were used in this work. The first DNA molecule consisted of a closed double helix 262 bp in length and a cruciform with restricted mobility (Fig. 1b). This is a tetramobile junction, because 4 bp at the base of each hairpin of the molecule are homologous, so they can be transformed into 8 bp of the circle by branch migration. Two other cruciforms were constructed with immobile junctions, corresponding to the extrema of the excursions of the tetramobile junction (also shown in schematic form in Fig. 1b). We will refer to these species as tetramobile, extruded immobile and intruded immobile cruciforms. In addition, a circular DNA molecule with perfect strand complementarity and the same total length was prepared.

A set of closed circular DNA molecules with different linking number (Lk) values usually appeared after cyclization of linear molecules. In our case of very short DNA circles the set could contain only very few topoisomers (17,18). We detected only one topoisomer for the extruded immobile cruciform and two topoisomers for the tetramobile and intruded immobile cruciforms. Analysis of denaturing gel mobilities combined with theoretical treatment showed that the Lk values were 25 and 26 for the molecules with two topoisomers and 25 for the only topoisomer of the extruded immobile cruciform (13). The mobility of the topoisomers was nearly identical on non-denaturing polyacrylamide gels; Figure 2a shows that they moved as a single band, except for the intruded species, which does resolve. Interestingly, in the absence of ethidium the molecules containing cruciforms migrated more rapidly than a simple DNA circle of the same length also shown on the gel.


Figure 2. Autoradiograms illustrating the transition described here. Each of these 5% non-denaturing gels is organized in the same fashion. Starting at the left, there is a lane of linear markers (LM), then lanes containing the extruded immobile cruciform (E), the tetramobile cruciform (T) and the intruded immobile cruciform (I) and a double-helical circle of the same length as the other molecules (D). To the right of these lanes are four lanes containing nicked versions of these same species respectively (En, Tn, In and Dn). Beneath each gel we have included a box that contains the ethidium bromide (EB) concentration and our interpretation of the contents of each of the experimental lanes. The species are indicated by their linking number, Lk (25 or 26); in addition, we have attached labels to indicate whether the band contains the molecule before (represented by B) or after (represented by A) the transition described here. In (a) we see that there is no resolution of E or T topoisomers, but I is resolved into topoisomers. In (b) the topoisomers of the tetramobile cruciform and the intruded cruciform are well resolved. In (c) we see the appearance of a new, slowly migrating species (indicated in the explanatory box as 26A), corresponding to a transition of the tetramobile and the intruded immobile cruciforms in the topoisomers with Lk = 26. In (d) the transition in the higher Lk topoisomers of the tetramobile and intruded immobile cruciforms is complete and those species are seen as the middle band in those lanes (indicated in the explanatory box as 26A). However, the extruded immobile cruciform and the lower Lk topoisomers of the tetramobile and intruded immobile cruciforms are seen partway through their transitions; the highest mobility bands (indicated in the explanatory box as 25B) correspond to molecules that have not undergone the transition and the lowest mobility bands (indicated in the explanatory box as 25A) correspond to those molecules that have undergone the transition. In (e) the three species have completed the transition. The linking number corresponding to the double helical circle is indicated to be 28; this molecule never undergoes the transition. Note that in the presence of ethidium the nicked species all exhibit mobilities distinct from those of the experimental species, indicating that the transition is unrelated to nicking.

However, adding 0.1 µM ethidium bromide (EtBr) led to their separation on the gel (Fig. 2b). A theoretical treatment of EtBr binding shows that all topoisomers have to be positively supercoiled under these conditions (see below). Consequently, the topoisomers with higher Lk values should move faster in the gel. The branchpoint position for the tetramobile cruciforms will be intruded (13) and thus the mobility of the topoisomers of the tetramobile cruciform and the intruded immobile cruciform must be the same. This is exactly what we see in Figure 2b. Note that the relative amounts of the two topoisomers are different for these DNA species. The difference results from variable branchpoint positions in the tetramobile cruciform during cyclization. In contrast, the extruded immobile cruciform molecules have only a single branchpoint position, despite torsional pressure; the mobility of the topoisomer does not match the topoisomer mobility of the other two molecules.

We have included intentionally nicked species in separate lanes in each of the gels. The point of this addition is to ensure that the extra species or altered mobility species are not nicked DNA, possibly resulting from the presence of ethidium. The mobilities of the nicked molecules are distinct from the experimental species in all gels in Figure 2 that contain ethidium, hence the phenomena that we report here are unrelated to DNA nicking.

When the EtBr concentration in the gel was increased to 0.5 µM positive torsional stress was correspondingly increased. Under these conditions the band corresponding to the topoisomer with higher Lk split into two bands for the tetramobile and intruded immobile cruciforms (Fig. 2c). This is a direct indication that the topoisomer adopts two different conformations and that the time of interconversion between these conformations is larger than the time of gel electrophoresis (3 h). Similar splitting of a topoisomer band has been observed for cruciform extrusion in palindrome sequences under the action of negative supercoiling (19-21). It has been shown directly that cruciform extrusion can take many hours at room temperature (22-24). We conclude that formation of a new structure, probably from the cruciforms, in our DNA molecules takes >3 h (the electrophoresis time) under this torsional stress. We have ensured that we are observing an equilibrium distribution of conformers: Heating the intruded species at 65°C for 30 min had no effect upon the observed distribution of conformers (data not shown). The only topoisomer of the extruded immobile cruciform is less supercoiled and its cruciform is stable under these conditions.

When the concentration of EtBr was tripled to 1.5 µM a second band for the DNA with the extruded immobile junction appeared (Fig. 2d). This corresponds to the transition in the only topoisomer of the extruded cruciform molecules. Although there were still three bands for DNA molecules containing the tetramobile and intruded immobile cruciforms, the states of the topoisomers were different at this EtBr concentration. For these two DNA molecules the transition in the topoisomer with higher Lk had been completed; we see splitting of the band for the topoisomers with lower Lk. This interpretation follows from analysis of the intensity distribution between the bands for the two DNA species. Indeed, in both cases the relative intensity of the second band corresponded well to the relative amount of the topoisomer with higher Lk.

The pattern of the bands became simple again in 5 µM EtBr. At this ethidium concentration the transition was complete in all topoisomers (Fig. 2e). Each topoisomer formed a separate single band at this ethidium concentration and even at 17 µM EtBr (data not shown). Thus we conclude that the transition in these supercoiled minicircles occurs in a range of EtBr concentrations between 0.3 and 2.5 µM.

In order to estimate the helical repeat of the new structures observed here we compared the electrophoretic mobilities of these molecules with those of a completely complementary circular closed molecule containing the same number of nucleotides, as shown in Figure 3. This gel was run in the presence of 15 µM ethidium, to ensure that the transition was complete. We assign a linking number of 28 to this species by the following argument. The linking numbers of the two intruded species were previously characterized to be 25 and 26 (13). The difference in length between the circular region of the intruded molecules and the completely complementary species is 28 nucleotide pairs. Thus the topoisomer distribution should be shifted relative to the intruded species by ~28/10.5, or 2.7. Therefore, for the perfect circles the linking numbers of the topoisomers must be 28 and, maybe, 29, although the first must dominate. We observe only a single topoisomer for the completely complementary species, so its linking number must be 28.


Figure 3. Electrophoretic mobilities of post-transitional species. Gel conditions and conventions are similar to those in Figure 2, except that this gel contains 15 µM ethidium bromide, to ensure that the transition is complete. The left three lanes contain the nicked extruded (En), nicked tetramobile (Tn) and intruded (In) molecules; the next three lanes contain the experimental species, extruded (E), tetramobile (T) and intruded (I). The rightmost lane contains the nicked double-helical circle (Dn), the one to its left contains the un-nicked double-helical circle (D) and the one to the left of that contains a mixture of double-helical circles that have been closed in the presence of varied amounts of ethidium to produce a series of topoisomers (Dt). Linking numbers of the Dt species are indicated both at the right and at the bottom. It is clear that lanes E, T and I all contain molecules that migrate similarly to the Dt species with Lk = 25 and that T and I contain molecules that migrate similarly to the Dt species with Lk = 26. Bands at the very top of each lane correspond to material that has remained in the well, failing to penetrate the gel.

In addition to this topoisomer, we prepared a series of topoisomers with lower linking numbers by ligating it in the presence of varied amounts of ethidium (seen in the lane labeled Dt in Figure 3). We know that the species in this lane represent the complete set of topoisomers with successive linking numbers, because we have sampled the titration of the circle with ethidium at points that produce pairs of topoisomers. The values of the linking numbers for the different samples overlapped, so we are certain that there are no topoisomers missing from the final mixture.

The mobilities in lane Dt are very similar to those of the topoisomers with the same linking number for the extruded, tetramobile and intruded species. This finding suggests that the interwinding of perfectly complementary DNA is very similar to the interwinding of DNA molecules that are designed not to be complementary. The extruded molecule would, if perfectly aligned, contain four complementary G-C nucleotide pairs out of 36 positions; the intruded and tetramobile species contain the same four complementary G-C pairs out of 28 positions. The similarities in mobilities indicate that the writhes of the extruded, tetramobile and intruded molecules are similar to that of the completely complementary molecule. Consequently, those molecules with the same linking number have the same total twist and the region whose sequence has been varied makes the same contribution to the twist in each of the species.

DISCUSSION

We have observed a conformational transition in synthetic DNA minicircles containing stable cruciform structures. This transition was caused by positive torsional stress induced by the binding of ethidium to the minicircles. This means that under torsional stress the minicircles adopted conformations with higher `equilibrium' twist than they had had initially and that this change occurred in the initially branched portions of the molecules. Indeed, we have shown that a perfectly paired DNA circle does not demonstrate this transition (lane D in Fig. 2). Denaturation of the hairpins and successive interwinding of their single-stranded components would certainly decrease the torsional stress in the molecules. As a result, the molecular writhe must also diminish and therefore the mobility of the molecules on the gels decreases. It is worth noting that the contribution of the hairpins to the linking number of the DNA strands is zero.

We have used different concentrations of EtBr to introduce a positive torsional stress into the minicircles. It is interesting to estimate the superhelix density needed to cause the transition. To do this we need to calculate the amount of EtBr bound to our DNA molecules. Binding of EtBr to supercoiled DNA is well described by the excluded site model, which accounts for the change in supercoiling free energy as a result of ligand binding (25). Statistical mechanical treatment of the model gives the following equation for the number of bound EtBr molecules per base pair, [nu]
1

where K is the equilibrium binding constant of EtBr with linear DNA, c is the concentration of free EtBr in solution, A is a constant specifying the free energy of supercoiling, which depends on the DNA length, and [sigma] is the DNA superhelix density (25). The parameter [alpha] specifies the fractional unwinding (relative to the average twist) of the double helix upon ligand binding
2
where [Phi] = 26° is the angle of unwinding of the double helix resulting from binding of an EtBr molecule and [gamma] = 10.5 is the DNA helical repeat (26,27). Equation 1 can be solved numerically for any particular value of c.

There are two parameters in equation 1, K and A, which are known only approximately in our case. The binding constant K is known for a solution containing sodium ions (see 28; for a review see 29)
3

In the TBE buffer that we used in this work the sodium ions are a small fraction of all cations, present only as the counterions of EDTA. If we take into account only 4 mM Na+ in the buffer, the value of K should be ~107/M. If we suggest that the Tris cations in the buffer system might behave similarly to sodium cations we find from equation 3 the lower limit of K, 105/M. This limit is too low, probably because Tris ions are not as effective in screening DNA charges as sodium ions (30), and a lower limit of 106/M for K seems a more reasonable estimate.

Although the value of A for this DNA size has been found to be equal to 40 (17,18), the presence of the cruciform is likely to reduce the rigidity of the minicircles and the value of A along with it. We found earlier that A equals 18 for the minicircles with stable cruciforms (13). However, our analysis required additional assumptions and 18 should be considered as a lower limit for the value of A.

Thus we have two sets of K and A, corresponding to lower and upper limits of [nu] for any particular concentration of EtBr. Using these sets and solving equation 1 numerically we have estimated the effective superhelix density ([sigma] + [alpha][nu]) of both topoisomers of the molecules with mobile and intruded immobile junctions in the range of the transition (Table 1). We conclude from these data that the transition corresponds to a positive superhelix density in the range 0.04-0.1.

Table 1. Calculated effective superhelix density of the minicircles at different concentrations of EtBr
[EtBr] (µM) Effective superhelix density ([sigma] + [alpha][nu])
  Lk = 25 Lk = 26
  Lower limit Higher limit Lower limit Higher limit
0.0 -0.020 -0.020 0.190 0.190
0.1 0.012 0.061 0.030 0.076
0.5 0.030 0.096 0.043 0.109
1.5 0.043 0.121 0.055 0.133
5.0 0.058 0.148 0.068 0.160
The lower and higher limits of [sigma] + [alpha][nu] for two topoisomers of the molecules with mobile and intruded immobile junctions were obtained by numerical solution of equation 1. The lower limit values were obtained for K = 106/M and A = 40, the higher limit for K = 107/M and A = 20. Superhelix density values in bold in the table correspond to EtBr concentrations in the range of the transition.

The electrophoretic mobility data in Figure 3 have enabled us to directly estimate interwinding of the opposite DNA strands in the post-transition structures. We found that the mobilities of all molecules, including perfectly complementary circles, depend only on their linking numbers, not on their sequences. This finding implies that the twist in the region where the sequences differ is close to that of B-DNA, regardless of the extent of its complementarity. More data are required to form conclusions on the extent of regularity in the interwound structure formed by non-complementary base pairs under positive torsional stress.

ACKNOWLEDGEMENTS

This research has been supported by grants GM-54215 (A.V.V.) and GM-29554 (N.C.S.) from the National Institute of General Medical Sciences, N000149810093 from the Office of Naval Research (N.C.S.), NSF-CCR-97-25021 from the National Science Foundation (N.C.S.) and by a Margaret and Herman Sokol Fellowship (X.Y.). We are grateful to Dr J.B.Chaires for valuable discussions about this work.

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*To whom correspondence should be addressed. Tel: +1 212 998 8395; Fax: +1 212 260 7905; Email: ned.seeman@nyu.edu

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