G-Quadruplex-Based Splice Switching as a Therapeutic Approach in Duchenne Muscular Dystrophy

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

RNA guanine (G)-quadruplexes (rG4) are unique noncanonical structures composed of stacked quadruplexes that play diverse roles in regulating gene expression, from transcription to protein synthesis. This study proposes a new splice-switching therapy using G-quadruplex-inducing antisense oligonucleotides (G-ASOs) reinstate dystrophin expression Duchenne muscular dystrophy (DMD) models. G-ASOs consist two functionally independent domains enable the formation RNA/DNA hetero-G-quadruplex (hG4) structures. The domain binds complementary sequences within target RNA, while G-rich domain, which contains sequence continuous guanines (G-tract), interacts with region form an hG4 structure. precise binding forms structure effectively interrupts alternative splicing. In contrast traditional methods block sterically, this technique employs steric hindrance by forming Significantly, our findings show can still even when and as much 70 nucleotides apart. To address challenges associated G-quadruplex via G-ASO self-assembly, we developed bulge-containing G-ASOs. enhancement improves both efficiency induction exon-skipping therapy. summary, highlights potential therapy, specifically DMD, marks significant progress development novel therapeutic strategies. These highlight effectiveness demonstrate advancements structural manipulation.

Language: Английский

Conformational Propensities of a DNA Hairpin with a Stem Sequence from the c-MYC Promoter

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 483 - 483

Published: March 26, 2025

G-quadruplexes and i-motifs are four-stranded non-canonical structures of DNA. They exist in the cell, where they implicated conformational regulation cellular events, such as transcription, translation, DNA replication, telomere homeostasis, genomic instability. Formation G-quadruplex i-motif conformations genome is controlled by their competition with pre-existing duplex. The fate that depends upon relative stabilities competing conformations, leading ultimately to a distribution double helical, tetrahelical, coiled conformationsthat coexist dynamic equilibrium each other. We previously developed CD spectroscopy-based procedure characterize adopted equimolar mixtures complementary G- C-rich strands from promoter regions c-MYC, VEGF, Bcl-2 oncogenes. In those bimolecular systems, duplex-to-tetraplex duplex-to-coil transitions accompanied strand separation an associated entropic cost. This situation distinct pseudo-monomolecular nature transformations within genome, does not occur. To mimic better we here extend our studies monomolecular construct—a hairpin—in which featuring sequences region c-MYC oncogene linked dT11 loop. used CD-based quantify states sampled hairpin at pH 5.0 7.0 function temperature concentration KCl. data were analyzed according thermodynamic model based on equilibria between different evaluate properties duplex-to-coil, G-quadruplex-to-coil, i-motif-to-coil hairpin. results have implications for modulation means therapeutic intervention.

Language: Английский

Polymeric Properties of Telomeric G-Quadruplex Multimers: Effects of Chemically Inert Crowders

Biomacromolecules, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

G-quadruplexes are noncanonical DNA structures rather ubiquitous in the human genome, which thought to play a crucial role development of majority cancers. Here, we present novel coarse-grained approach modeling that accounts for their structural flexibility. We apply it study polymeric properties G-quadruplex multimers, with and without crowder molecules, mimic vivo conditions. find that, contrary some suggestions found literature, long multimers flexible macromolecules, local persistence length comparable monomer size, exhibiting chain stiffness variation profile consistent real polymer good solvent. Moreover, crowded environment (up 10% volume fraction), report exhibit an increased propensity coiling, corresponding decrease measured stiffness.

Language: Английский