hnRNPA1/UP1 Unfolds G-Quadruplexes and Feeds a Regulatory Axis Controlling Gene Expression.

Recent studies have proven that the genetic landscape of pancreatic cancer is dominated by the oncogene. Its transcription is controlled by a G-rich motif (called 32R) located immediately upstream of the TSS. 32R may fold into a G-quadruplex (G4) in equilibrium between two G4 conformers: G9T ( = 61.

Structure of two G-quadruplexes in equilibrium in the KRAS promoter.

KRAS is one of the most mutated oncogenes and still considered an undruggable target. An alternative strategy would consist in targeting its gene rather than the protein, specifically the formation of G-quadruplexes (G4) in its promoter. G4 are secondary structures implicated in biological processes, which can be formed among G-rich DNA (or RNA) sequences.

Phenanthroline polyazamacrocycles as G-quadruplex DNA binders.

Targeting quadruplex DNA structures with small molecules is a promising strategy for anti-cancer drug design. Four phenanthroline polyazamacrocycles were studied for their binding affinity, thermal stabilization, inhibitory effect on the activity of helicase towards human telomeric 22AG and oncogene promoter c-MYC G-quadruplexes (G4s), and their ability to inhibit Taq polymerase-mediated DNA extension. The fluorescence resonance energy transfer (FRET) melting assay indicates that the melting temperature increases (ΔTm values) of c-MYC and 22AG G4s are 17.

Unexpected Position-Dependent Effects of Ribose G-Quartets in G-Quadruplexes.

To understand the role of ribose G-quartets and how they affect the properties of G-quadruplex structures, we studied three systems in which one, two, three, or four deoxyribose G-quartets were substituted with ribose G-quartets. These systems were a parallel DNA intramolecular G-quadruplex, d(TTGGGTGGGTTGGGTGGGTT), and two tetramolecular G-quadruplexes, d(TGGGT) and d(TGGGGT). Thermal denaturation experiments revealed that ribose G-quartets have position-dependent and cumulative effects on G-quadruplex stability.

G-quadruplexes unfolding by RHAU helicase.

G-quadruplexes (G4) are RNA and DNA secondary structures formed by the stacking of guanine quartets in guanine rich sequences. Quadruplex-prone motifs may be found in key genomic regions such as telomeres, ribosomal DNA, transcriptional activators and regulators or oncogene promoters. A number of proteins involved in various biological processes are able to interact with G4s.