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Platination of the (T2G4)4 telomeric sequence: a structural and cross-linking study
S Redon1, S Bombard, M A Elizondo-Riojas
1Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris V, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Biochemistry
|July 18, 2001
Summary
Potassium and sodium ions stabilize G-quadruplex structures more than lithium ions during platinum-based DNA platination. This study reveals cation-dependent G-quadruplex stability and platinum adduct formation in telomeric sequences.
Area of Science:
- Biochemistry
- Chemical Biology
- Structural Biology
Background:
- Telomeric sequences form G-quadruplex structures, which are important in DNA replication and stability.
- Platinum-based drugs are used in cancer therapy, and their interaction with DNA structures like G-quadruplexes is of significant interest.
- Cations play a crucial role in stabilizing G-quadruplex structures.
Purpose of the Study:
- To investigate the effect of different alkali metal cations (Li+, Na+, K+) on the platination of a specific telomeric G-quadruplex sequence.
- To identify the specific guanine residues involved in platinum adduct formation.
- To elucidate the influence of cation choice on the stability and structure of G-quadruplexes upon platination.
Main Methods:
- Platination of the telomeric sequence (T(2)G(4))(4) in aqueous solutions containing LiClO(4), NaClO(4), or KClO(4) using platinum complexes.
- Identification of platinum adducts and the specific guanine residues involved using analytical techniques.
- Restrained molecular dynamics (rMD) simulations to model and confirm G-quadruplex structures and platinum adducts.
Main Results:
- The relative stability of G-quadruplex structures was determined in the order K(+) > Na(+) >> Li(+).
- The tri-ammine platinum complex ([Pt(NH(3))(3)(H(2)O)](2+)) formed mono- and poly-platinated adducts primarily at G9 and G15.
- Bifunctional platinum complexes (cis- and trans-[Pt(NH(3))(2)(H(2)O)(2)](2+)) formed G3-G15 chelates and, with the trans isomer, bis-chelates at both ends of the G-quadruplex without significantly disturbing the structure.
Conclusions:
- Cations significantly influence the stability of G-quadruplex structures, with potassium providing the highest stability.
- The same G-quadruplex folding occurs across different cations, but their stabilities vary.
- Platinum adduct formation occurs at specific guanine sites, and bifunctional platinum complexes can form cross-links, with the trans isomer showing potential for structural integrity preservation.