Transcriptional control by G-quadruplexes: In vivo roles and perspectives for specific intervention

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

“…An early study hinting at the possibility of using G4 ligands as the basis to improve the selectivity of nucleic acid alkylating agents was reported in 2006 by Tan et al The authors demonstrated the G4 selectivity of compound 32 (Figure 17) derived from porphyrin, a known G4-binding chemotype. [138] Previously the compound exhibited toxicity in cervical cancer (HeLa) and liver cancer (HepG2) cells under photoirradiation, an effect tentatively attributed to the photoinduced formation of quinone methides (37) and subsequent alkylation of DNA (Scheme 2). However, it is unclear whether any such alkylation is G4 specific, or whether the toxic effects instead result from the generation of singlet oxygen (see Section 3.3).…”

“…[33] Meanwhile, progress in biology has delivered ever increasing evidence for the role of these sequences in life, from organism development, through to epigenetic regulation and their role in health and disease. [34,35] Indeed, various therapeutic hypotheses have been proposed, such as targeting G4s to inhibit the transcription of oncogenes [36,37] (Figure 2) or by targeting the G4 sequence in chromosome telomeres. [38] But this does not confine interest in G4 to the biological community alone; the precise folding of such structures into well-defined shapes and their polymorphism, that can be controlled by different conditions and stimuli, point to exciting Figure 2.…”

“…The folded G4 structure may also interfere with transcription factor binding, and examples of G4-targeting molecules that up-regulate certain genes are also known. [37] applications of these structures away from the biological milieu in the development of new responsive enzymes, [39][40][41][42] switches, [43,44] and functional materials. [45]…”

G-quadruplex–forming promoter sequences enable transcriptional activation in response to oxidative stress

“…Given the abundance of PQS in the promoter regions throughout the genome (12,13), the generality of the proposed mechanism may be very likely. Supporting this view is the fact that Fleming et al also provide a more comprehensive mechanistic explanation for the DNA oxidation and BER-dependent transcriptional activation reported in several cellular studies (4,10,11,21).…”

“…Non-Watson-Crick secondary structures of nucleic acids, and in particular, G4 structures in DNA is an area of extremely active research (12)(13)(14)(15)(16). Although G4 structures were initially described in the context of telomeres, recent genomic data revealed tens of thousands of sequences throughout the genome (14,17) that, in principle, could form G4 structures, called potential G-quadruplex-forming sequences (PQS).…”