Other Quadruplex Forming Sequences

2 Self Association of Watson-Crick Duplex Sequences to Form Tetraplexes 

Interest in G C tetrad forming base-pairs comes from the discovery of the fragile X syndrome and the associated d(CGG)n d(CCG) repeats. Initial structural prediction for the CG rich repeat sequences identified a parallel stranded motif stabilized by the methylation of the cytosine residues. Subsequent structural analyses by NMR methods on a sequence that contained CG2 repeats, linked by thymine bases, revealed a head-to-tail hairpin arrangement 

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Aside from telomeric sequences and c-myc, discussed elsewhere in this book, other known quadruplex-forming sequences include the fragile X syndrome repeat d(CGG) and the Cystatin B promoter, which has a region with sequence (CGCG4CG4)4 and is involved in epilepsy. G-rich strands of the... 

The two best-studied ions are Na" and K". The preference of quadruplex central cavity for potassium over sodium ions is the result of two opposite effects from one side the free energy of Na" binding to a quadruplex is more favourable than that of K, but from the other side this effect is more than compensated by the much greater cost of Na dehydration. " The net result is a free energy change in favour of the potassium form. The number of released ions upon melting of the human telomeric quadruplex can be estimated by melting experiments as 5 in the presence of NaCl and 6 in the presence of KCl. Note that this value should not be interpreted as the number of ions bound in the quadruplex channel, as the total number of ions released on thermal denaturation includes the ions bound in the quadruplex channel, and the difference between the number of ions condensed on the quadruplex and on the random coil. In our hands, the dilfer-ences in thermal stability between the sodium and potassium forms of a quadruplex are very sequence dependent values (Tni(K+) — Ln(Na+)) are... 

Telomeric repeats from other organisms are also prone to quadruplex polymorphism. The Tetrahymena TG4T2G4T telomeric sequence, for example, may adopt several conformations. This sequence forms two novel G-quadruplex structures in Na -containing solution. In the first structure (head-to-head), the two loops are at one end of the G-tetrad core in the second structure (head-to-tail), the two loops are located on opposite ends of the G-tetrad core. In contrast to the human telomere sequence, the proportions of the two forms are similar for a wide range of temperatures their unfolding rates are also similar, with an activation enthalpy of 37 kcal mol . The (G4T4) sequence may also interconvert between parallel and antiparallel structures. 

The reasons for the dramatic difference between the solution-state Na form and the crystal-state form of d[AGGG(TTAGGG)3] are yet to be fully elucidated major changes in structure have previously been noted in CD studies of the transition, although it had not been possible to assign structures to the individual species. On the other hand, several recent studies have demonstrated that an antiparallel G-quadruplex is formed by the human telomere repeat sequence in solution in the presence of both Na and... 

By virtue of its helix-loop-helix motif, MyoD is able to form homodimers, as well as heterodimers, with other ubiquitously expressed helix-loop-helix proteins, such as E12 and E47. MyoD-E-protein heterodimers bind to E-box DNA more tightly than MyoD homodimers and act as stronger activators of transcription. MyoD-E47 heterodimers were found to bind to bimolecular G-quadruplex structures more weakly than MyoD homodimers. Specifically, MyoD heterodimers bound more tightly to E-box DNA than to bimolecular G-quadruplex structures of promoter sequences of the sMtCK and ot7 integrin, as reflected by... 

In addition to the G-quadruplex other motifs that have been solved include the i-motif, a pH-dependent poly dA helix which forms the basis of a molecular switch, the HIV-1 TAR DNA hairpin, and the B-Z transition in a GC-rich DNA sequence. There are also many protein/ peptide structures that have been solved that have DNA as part of the recognition domain, including a zinc sensor, MetJ repressor, lac repressor, Lambda integrase protein, protection of telomers (Potl)... 

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