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c-kit2 G-quadruplex stabilized via a covalent probe: exploring G-quartet asymmetry
Kateřina Peterková1,2,3, Ivo Durník2,4, Radek Marek2,4,5
1Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
Nucleic Acids Research
|August 8, 2021
Summary
Pyrene (Upy) incorporation into G-quadruplex DNA stabilized terminal structures but caused polymorphism in loops. These findings offer insights into G-quadruplex interactions and potential anticancer applications.
Area of Science:
- Biochemistry
- Structural Biology
- Genomics
Background:
- G-quadruplex DNA structures are conserved in regulatory genomic regions and influence gene expression.
- Small polyaromatic molecules, like pyrene, can modulate G-quadruplex properties.
Purpose of the Study:
- To investigate the interaction of pyrene with G-rich DNA forming G-quadruplex structures.
- To explore how incorporating pyrene-modified deoxyuridine (Upy) affects G-quadruplex stability and structure.
Main Methods:
- Utilized a model system with a c-kit2 G-quadruplex sequence.
- Incorporated Upy at terminal positions and in the pentaloop.
- Performed Nuclear Magnetic Resonance (NMR) structural studies and molecular dynamic simulations.
Main Results:
- Upy incorporation in the pentaloop induced structural polymorphism and potential thermal destabilization.
- Upy substitution at terminal positions led to significant thermodynamic stabilization.
- Stabilization resulted from pi-pi stacking between pyrene and guanine nucleotides in G-quartets.
- The resulting structures mimicked the human KIT proto-oncogene G-quadruplex.
Conclusions:
- The position of pyrene modification dictates its effect on G-quadruplex structure and stability.
- Terminal pyrene incorporation offers a strategy for stabilizing G-quadruplex structures.
- These stabilized structures hold potential for antiproliferative effects against cancer cells.
