DNA triplex and quadruplex

Shafer, RH (1998) Stability and structure of model DNA triplexes and quadruplexes and their interactions with small ligands. Prog. Nucleic Acid Bes. Mol. Biol. 59, 55-94. 

J. Feigon, K.M. Koshlap and F.W. Smith, H NMR spectroscopy of DNA triplexes and quadruplexes, Nucl. Magn. Reson. Nucleic Acids, 1995, 261, 225-255. 

Abstract The physical aspects of DNA structure and function are overviewed. Major DNA structures are described, which include the canonical Watson-Crick double helix (B form), B , A, Z duplex forms, parallel-stranded DNA, triplexes and quadruplexes. Theoretical models, which are used to treat DNA, are considered with special emphasis on the elastic-rod model. DNA topology, supercoiling and their biological significance are extensively discussed. Recent developments in the understanding of molecular interactions responsible for the stability of the DNA double helix are presented. 

Competitive equilibria between DNA triplex and quadruplex the role of the G-quartets... 

In addition to the major double-helical form, DNA also exists as triplexes and quadruplexes and forms complex three-way or four-way junctions. Single-stranded DNA has been shown in vitro to fold into complex, stable three-dimensional folds and to bind to smah molecules (such DNA molecules are named aptamers) or to catalyze reactions in a way similar to proteins (so-caUed deoxyribozymes or DNAzymes) [4]. This increased structural diversity makes it a more attractive host molecule for hybrid catalysis [5]. Furthermore, directed evolution approaches are easier to conduct with nucleic acids than with proteins, as nucleic acids can be directly rephcated and amphfied. 

The RADACK (contraction of RADiation-induced attACK) model, that we have developed [9,10], accounts for the experimentally determined probabilities of radiolytic damages caused by the OH radical attack in all forms of DNA (B [11], Z [12], triplex [13], quadruplex [14]), in DNA-protein complexes [15] and has the potential to predict radiolytic attack probabilities in other molecules or assemblies. Direct ionisation effects are not taken into account. The determination of relative probabilities of reaction ofthe target with the OH radicals takes into account two factors 1) the accessibility of the reactive sites of the target since it uses the exact tridimensional structure of the macromolecule or assembly as determined by NMR, crystallography or as built up by molecular modelling, and 2) the chemical reactivity of the residues (nucleotides or amino-acids). 

FIGURE 9.14 Variant forms of DNA. (a) A cruciform, a triplex, and Z-DNA (top to bottom), (b) A quadruplex formed when repeated guanine bases align two DNA strands. Images courtesy of KM. Vasquez. From G. Wang and K.M. Vasquez, Mutation Research >2006 Elsevier. 

Figure 27. Visualization of biomesogenic nucleic-acid selforganizations by molecular-resolving microscopies (top to bottom and left to right) nucleic acid strand patterns B-DNA and A-RNA duplexes, DNA/ RNA triplex, G-quadruplex, DNA/RNA-duplex/pro-tein-)3-sheet complexations STM and SFM-investi-gations of nucleic acid organizational behavior DNA-plasmid [74 c] RNA- and RNA/peptide-organiza-tions (U) (A) -duplexes (U) (A) (U) -tri-plexes (G) -quadruplexes, (L-Lys) /(U) (A) -com-plexes in 2D and 3D representation [7 a, 17, 18, 33 a, c, f, p, q, 75].

More than 10 different types of non-canonical DNA structure have been reported so far, including Z-DNA, A-motif, tetraplex (G-quadruplex and i-motif), hairpin, cruciform, and triplex, and their structures have been described in several reviews. Here, five typical non-canonical DNA structures will be... 

The tertiary structure of DNA is the structural level that is most relevant to 3-D reality. Traditionally, ODNs in a physiologically relevant aqueous solution are considered to be in a random-coiled ssDNA state or in the form of dsDNA helix in the presence of a complementary DNA, including the case of self-complementarity. The double helix is the dominant tertiary structure for biological DNA that can be in one of the three DNA conformations found in nature, A-DNA, B-DNA, and Z-DNA. The B-conformation described by Watson and Crick (11) is believed to predominate in cells (12). However other types of nucleic acid tertiary structures different from random or classical double-stranded helix forms can also be observed. Among them are triplexes, quadruplexes, and several other nucleic acid structures (13, 14). 

DNA showed that there might be a biological consequence to oxidation of telomeric DNA. Telomeric DNA contains GGG sequences, and telomeres adopt a quadruplex structure. Oxidation of the 5 -G resulted in a quadruplex structure, but oxidation in the middle of the GGG triplex led to multiple structures. Telomerase activity was significantly reduced when 8-oxo-dG was at the 5 -end of the triplet, but not in the middle where multiple structures were formed. 

Electron transfer has primarily been studied with DNA duplexes, but there are higher order structures that have been examined. Triplexes have been studied where it was shown that transfer to the third strand occurs. In quadruplex structures more damage occurs at the external tetrads, and quad-ruplex guanines are more effective traps than when in a duplex. Charge transfer has also been examined with three-way " and four-way junctions. DNA bound to electrode surfaces has been used to study the electrochemical... 

There are several examples of multiplexed SERRS measurements as apphed to DNA assays [69, 70, 73, 77, 84—89] reported in the literature and a few examples of immunoassays. Thus Woo et al. [90] described a triplex immunoassay for the detection of bronchioalveolar stem ceUs, Cui et al. [91] used two dye labels to carry out a duplex sandwich immunoassay, Jun et al. [92] reported a triplex immunoassay using SERS, and Lutz et al. [93] described a quadruplex platelet activity state plate binding assay. 

Figure 4.7. Representations of some unusual higher order DNA structures triple helix (triplex), in which a third DNA strand hydrogen-bonds in the major groove of a double-stranded DNA a hairpin, in which a single strand of DNA hydrogen-bonds with itself to make a stem and nonpaired bases are pushed out to form a loop a tetraplex (quadruplex), in which (in this case) a single strand of DNA folds over on itself in an unusual G-G-G-G hydrogen bonding pattern, important in telomeric structure at the ends of chromosomes and a Holliday junction, in which four single strands of DNA base pair as usual but form this unusual complex structure, believed to be a good model for DNA recombination.

Tetraplex (= quadruplex) DNA (Fig. 4.9 and 4.12) has also been a target for detection by photophysical probes. The fluorescence of the dye DODC (see above) was found to be quenched by hairpin tetraplex DNA but not single-stranded DNA, duplex DNA, or parallel-stranded tetraplexes [326]. However, a later study found that triplex DNA competed very well with tetraplex DNA for DODC binding [322], The nature of the binding of DODC to these nucleic acid structures has not been clarified [322, 326]. 

Figure 2. Various DNA structures, (a) B-DNA (b) Z-DNA (c) intennolecular triplex (d) cruciform (e) H-DNA (intramolecular triplex) (f) G-quadruplex and its various foldings.

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