Structure of the Human Telomere in K⁺ Solution: A Stable Basket-Type G-Quadruplex with Only Two G-Tetrad Layers

Abstract

Previously, it has been reported that human telomeric DNA sequences could adopt in different experimental conditions four different intramolecular G-quadruplexes each involving three G-tetrad layers, namely Na + -solution antiparallel-stranded basket form, K + -crystal parallel-stranded propeller form, K + -solution (3+1) Form 1 and K + -solution (3+1) Form 2. Here we present a new intramolecular G-quadruplex adopted by a four-repeat human telomeric sequence in K + solution (Form 3). This structure is a basket-type G-quadruplex with only two G-tetrad layers: loops are successively edgewise, diagonal and edgewise; glycosidic conformations of guanines are syn•syn•anti•anti around each tetrad; each strand of the core has both a parallel and an antiparallel adjacent strands; there are one narrow, one wide and two medium grooves. Despite the presence of only two G-tetrads in the core, this structure is more stable than the three-G-tetrad intramolecular G-quadruplexes previously observed for human telomeric sequences in K + solution. Detailed structural elucidation of Form 3 revealed extensive base pairing and stacking in the loops capping both ends of the G-tetrad core, which might explain the high stability of the structure. This novel structure highlights the conformational heterogeneity of human telomeric DNA. It revealed a new folding principle for Gquadruplexes and suggests new loop sequences and structures for targeting in human telomeric DNA.

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“…Interestingly, both HRCC in Na ϩ and KSS in K ϩ displayed two positive peaks around 295 and 260 nm. These spectra are similar to those reported previously for the G-rich hTERT promoter, implying the coexistence of two different G-quadruplex conformations (41). Furthermore, the thermal difference spectra of all three sequences showed a negative peak around 295 nm and two …”

An RNA G-quadruplex in the 3' UTR of the proto-oncogene PIM1 represses translation

“…C3'-endo type of sugar pucker in RNA generally disfavors syn-conformation in guanosines making it difficult for RNA quadruplexes to adopt anti-parallel topology 21 unlike DNA quadruplexes which can adopt different topologies. [22][23][24][25][26][27][28] A mutant in which several guanines have been replaced by adenines did not show any characteristic signature for quadruplex formation (Fig. 1A).…”

Potential uses of G-quadruplex-forming aptamers

“…A typical antiparallel structure reaches the ratio of 1.0; e.g. thrombin binding aptamer d [GGTTGGTGTGGTTGG], and human telomeric repeat d[AGGG(TTAGGG) 3 ] in Na + (Macaya et al 1993;Lim et al 2009;Russo Krauss et al 2011). In this conformer clear positive and negative peaks to be observed at 295 nm and 240 nm respectively.…”