Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics

Abstract

Guanine-rich DNA sequences can form G-quadruplexes stabilized by stacked G–G–G–G tetrads in monovalent cation-containing solution. The length and number of individual G-tracts and the length and sequence context of linker residues define the diverse topologies adopted by G-quadruplexes. The review highlights recent solution NMR-based G-quadruplex structures formed by the four-repeat human telomere in K+ solution and the guanine-rich strands of c-myc, c-kit and variant bcl-2 oncogenic promoters, as well as a bimolecular G-quadruplex that targets HIV-1 integrase. Such structure determinations have helped to identify unanticipated scaffolds such as interlocked G-quadruplexes, as well as novel topologies represented by double-chain-reversal and V-shaped loops, triads, mixed tetrads, adenine-mediated pentads and hexads and snap-back G-tetrad alignments. The review also highlights the recent identification of guanine-rich sequences positioned adjacent to translation start sites in 5′-untranslated regions (5′-UTRs) of RNA oncogenic sequences. The activity of the enzyme telomerase, which maintains telomere length, can be negatively regulated through G-quadruplex formation at telomeric ends. The review evaluates progress related to ongoing efforts to identify small molecule drugs that bind and stabilize distinct G-quadruplex scaffolds associated with telomeric and oncogenic sequences, and outlines progress towards identifying recognition principles based on several X-ray-based structures of ligand–G-quadruplex complexes.

Probing Human Telomeric DNA and RNA Topology and Ligand Binding in a Cellular Model by Using Responsive Fluorescent Nucleoside Probes

“…Telomeric DNA, which end‐caps and protects the chromosomes from degradation and fusion, has been implicated in carcinogenesis and ageing‐related diseases 6. Biochemical investigations with GQ‐stabilizing ligands suggest that telomeric DNA uses this structural element to carry out its function.…”

“…In the human genome, GQ‐forming sequences are mostly found in the telomeric region (e.g., telomeric DNA and RNA repeats) and in several DNA promoters (e.g., C‐myc, C‐kit) and untranslated regions of mRNA (e.g., NRAS, BCL‐2) 3, 4. Recent biochemical investigations indicate that these G‐rich sequences play crucial roles in cellular processes, such as chromosome maintenance, as well as transcriptional and translational regulation of several protooncogenes, which have been found to be in consensus with the ability of these sequences to form stable GQ structures in vitro 5, 6. Consequently, stabilization of GQ structures by small‐molecule ligands has emerged as a novel approach to cancer therapeutics 7.…”

Targeting G-Quadruplex DNA with Small Molecules

“…The development of small molecules that specifically bind to a particular DNA secondary structure may improve cancer-specific targeting and decrease the side effects associated with chemotherapeutic treatments. G-quadruplex DNA structures are highly attractive targets given the abundance of detailed information available regarding their structures, [20,21] thermodynamic stabilities, [22] and potential biological activities -some of which might be considered cancer-specific. [21,31,[33][34][35]46] A growing number of groups are targeting G-quadruplex DNA with small molecules hoping to inhibit cancer growth according to two distinct mechanisms (Fig.…”

“…2). [20][21][22][23][24][25][26] Two of the 26 (or more) examples of intramolecular G-quadruplex topologies are shown in Fig 2. [21,27] While Gquadruplexes can exhibit thermodynamic stabilities comparable to those of the corresponding duplex structures, [19,[28][29][30] the presence and function(s) of these structures in vivo remains an open question. Intermolecular G-quadruplex structures have been proposed as intermediates or precursors of recombination and/or viral integration, [23,31,32] while intramolecular Gquadruplexes have been implicated in the regulation of gene expression and chromosome stability.…”

G-quadruplexes: selective DNA targeting for cancer therapeutics?

“…These elements are nonclassical four-stranded secondary structures arising from the folding of a single DNA strand that comprises stretches of tandem guanines [5]. …”