Sequence variant (CTAGGG)n in the human telomere favors a G-quadruplex structure containing a G·C·G·C tetrad

Abstract

Short contiguous arrays of variant CTAGGG repeats in the human telomere are unstable in the male germline and somatic cells, suggesting formation of unusual structures by this repeat type. Here, we report on the structure of an intramolecular G-quadruplex formed by DNA sequences containing four human telomeric variant CTAGGG repeats in potassium solution. Our results reveal a new robust antiparallel G-quadruplex fold involving two G-tetrads sandwiched between a G·C base pair and a G·C·G·C tetrad, which could represent a new platform for drug design targeted to human telomeric DNA.

DNA quadruplex folding formalism – A tutorial on quadruplex topologies

“…A greater number of stacking possibilities have been experimentally determined in this group: (a) (ÀlÀlÀl) as a two-stacked topology [23], (b) (+l+l+l) as the two-stacked 2KM3 [41] and 148D [42], (c) (Àld+l) as the four-stacked 201D [22], the three-stacked 143D [16] and the two-stacked 2KF8 [20] and 2KKA [21], and (d) (+ldÀl) as the twostacked 2KOW [43].…”

Screening of a Chemical Library by HT-G4-FID for Discovery of Selective G-quadruplex Binders

“…The test was performed with seven G4-DNA sequences and a control duplex DNA (ds26). The G4-DNA sequences, which display various structures, are 22AG (human telomeric repeat) [24], 21CTA (modified human telomeric sequence) [25], c-myc [26] and c-kit1 [27] (2 human proto-oncogene promoter sequences), TBA (the thrombin binding aptamer sequence) [28], Ceb1 and Ceb25 (2 human minisatellites sequences) [29]. It is worth noting that virtually all G4 and duplex DNA and RNA sequences may be used with this method, provided that the fluorescence enhancement of the bound TO is of sufficient intensity.…”

Dynamics of Fluorescent Dyes Attached to G‐Quadruplex DNA and their Effect on FRET Experiments

“…The structure with sequence 5'-A-GGGCTA-GGGCTA-GGGCTA-GGG-3' used in this studyw as described by Lim et al in 2009 (PDB ID 2KM3). [20] This particular fold was chosen because the presence of the variant repeatC TAGGG in KCl solution resultsi no ne uniquea ntiparallel conformation, [20] whereas the wild-type TTAGGG-repeat G-quadruplexes tend to fold into several different conformations rathert han as ingle favored arrangement. Figure2 shows the 2KM3 fold in more detail.…”

“…The stabilityo ft his fold is comparable to those of G-quadruplexes containing three G-quartets due to the tetrad and the C11-G14 base pair. [20] The dyes studied here are illustrated in Figure2.T hey exist either with or without sulfonate substituents and are tethered to the 3' end of the G-quadruplex (G22) through as hort amidite linker or al ong, six-carbon N-hydroxy- The subscript si ndicates that the dye is sulfonateda nd short/longr efers to the type of linker. The ring system attached to the DNA is highlighted in light gray and is referredt oa st he As ide of the dye,w hereas the nonattached dark gray ring system is referred to as the nA side.…”