G-quadruplex nucleic acids as therapeutic targets - PubMed (original) (raw)

G-quadruplex nucleic acids as therapeutic targets

Shankar Balasubramanian et al. Curr Opin Chem Biol. 2009 Jun.

Abstract

Nucleic acid sequences containing several short runs of guanine nucleotides can form complex higher order structures, termed quadruplexes. Their occurrence has been most extensively characterised at the telomeric ends of eukaryotic chromosomes, whose DNA comprises such sequences, and where the extreme 3' ends are single-stranded. This enables relatively facile formation of quadruplex arrangements under the influence of a quadruplex-selective small molecule to compete effectively with telomeric protein-DNA interactions. Occurrences of quadruplexes within the human and other genomes have been mapped by bioinformatics surveys, which have revealed over-representations in promoter regions, especially of genes involved in replication, such as oncogenes, as well as in 5'UTR regions. The highly distinctive nature of quadruplex topologies suggests that they can act as novel therapeutic targets, for example in the selective inhibition of transcription of a given oncogene, using designed small molecules to stabilise a particular quadruplex. This offers the prospect of an alternative to, for example, direct kinase targeting with small molecules, without the attendant issues of active-site resistance. We survey here the basis of these approaches, together with current progress, and discuss the mechanistic issues posed by quadruplex targeting.

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Figures

Figure 1

Figure 1

Structures of three quadruplex-forming ligands for which in vivo data have been reported.

figure 2

figure 2

Schematic of the cellular consequences of inducing quadruplex formation by means of a small-molecule ligand within the single-stranded telomeric DNA overhang at the 3′ end of a cancer cell chromosome. The single-strand binding protein hPOT1 is displaced from the overhang by quadruplex formation, so that recognition of the overhang by the RNA subunit of telomerase (hTR) action is impaired, telomerase-catalysed synthesis of telomeric DNA repeats is inhibited and telomeric DNA is shortened. The unmasking of the overhang from associated proteins can also lead to a DNA damage response.

Figure 3

Figure 3

Schematic of the promoter-G-quadruplex hypothesis. G-quadruplex-forming sequence motifs in the upstream (promoter) region (in green) of genes (in red) may fold into G-quadruplex structures. The formation of G-quadruplex, rather than duplex, DNA structure in the promoter is associated with an altered state of transcription. This hypothesis would suggest that any molecule capable of interacting with the specific G-quadruplex could modulate the transcriptional activity of the associated gene.

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