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Updated: Sep 29, 2025
Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
Polymorphic and Higher-Order G-Quadruplexes as Possible Transcription Regulators: Novel Perspectives for Future
Riccardo Rigo1,2, Elisabetta Groaz1,3, Claudia Sissi1
1Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Marzolo 5, 35131 Padova, Italy.
Abstract:
In the past two decades, significant efforts have been put into designing small molecules to target selected genomic sites where DNA conformational rearrangements control gene expression. G-rich sequences at oncogene promoters are considered good points of intervention since, under specific environmental conditions, they can fold into non-canonical tetrahelical structures known as G-quadruplexes. However, emerging evidence points to a frequent lack of correlation between small molecule targeting of G-quadruplexes at gene promoters and the expression of the associated protein, which hampers pharmaceutical applications. The wide genomic localization of G-quadruplexes along with their highly polymorphic behavior may account for this scenario, suggesting the need for more focused drug design strategies. Here, we will summarize the G4 structural features that can be considered to fulfill this goal. In particular, by comparing a telomeric sequence with the well-characterized G-rich domain of the KIT promoter, we will address how multiple secondary structures might cooperate to control genome architecture at a higher level. If this holds true, the link between drug-DNA complex formation and the associated cellular effects will need to be revisited.
Insights
Small molecules targeting G-quadruplexes (G4) in DNA show poor correlation with gene expression changes. Understanding G4 structural diversity is crucial for developing effective drugs targeting oncogene promoters.
Area of Science:
- Genomic structural biology
- Medicinal chemistry
- Cancer genomics
Background:
- Small molecules are designed to target G-rich DNA sequences that form G-quadruplexes (G4) at oncogene promoters to control gene expression.
- A frequent lack of correlation between G4-targeting small molecules and protein expression hinders pharmaceutical applications.
- The broad genomic distribution and polymorphic nature of G4 structures contribute to this challenge.
Purpose of the Study:
- To summarize G4 structural features for improved drug design strategies.
- To investigate how multiple G4 secondary structures cooperate in genome architecture.
- To re-evaluate the link between drug-DNA complex formation and cellular effects.
Main Methods:
- Comparative analysis of G4 structures, including a telomeric sequence and the KIT promoter G-rich domain.
- Review of existing literature on G4 targeting small molecules and their cellular effects.
Main Results:
- G4 structures exhibit significant polymorphism and wide genomic localization.
- The interplay between different G4 secondary structures may influence genome architecture.
- Current strategies for targeting G4s may require refinement due to structural complexity.
Conclusions:
- Focused drug design strategies considering G4 structural features are needed.
- Understanding cooperative effects of multiple G4 structures is essential for predicting cellular outcomes.
- Revisiting the correlation between G4-DNA complex formation and biological effects is critical for therapeutic development.
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