Biochemical and Biophysical Research Communications
DNA adducts of the enantiomers of the Pt(II) complexes of the ahaz ligand (ahaz = 3-aminohexahydroazepine) and recognition of these adducts by HMG domain proteins
Section snippets
Methods
Materials. [PtCl2(R-ahaz)] and [PtCl2(S-ahaz)] were prepared and characterized as described previously [9]. Cisplatin was obtained from Sigma (Prague, Czech Republic). The stock solutions of platinum compounds were prepared at the concentration of 5 × 10−4 M in 10 mM NaClO4 and stored at 4 °C in the dark. The synthetic oligodeoxyribonucleotides were synthesized and purified as described previously [10]. The duplexes (for their sequences, see Fig. 2, Fig. 3 and the text) uniquely and
Recognition by HMGB1 proteins
An important feature of the mechanism of action of cisplatin is that the major adducts of this platinum drug [1,2-GG intrastrand cross-links (CLs)] are recognized by proteins containing HMG domains [23], [24], [25]. Importantly, DNA modified by transplatin or monodentate platinum(II) compounds, such as [PtCl(dien)]+ (dien = N-(2-aminoethyl)ethane-1,2-diamine) or [PtCl(NH3)3]+, is not recognized by these cellular proteins [26]. It has been shown [23], [27] that the binding of these proteins to DNA
Discussion
As shown for the 1,2-GG intrastrand CL of cisplatin [32], [42], [43] HMGB1a binds to DNA around the site of this adduct in the minor groove while the amine ligands coordinated to platinum reside in the major groove. It is therefore unlikely that the different affinity of HMGB1a to the 1,2-GG intrastrand CLs of [PtCl2(R-ahaz)] and [PtCl2(S-ahaz)] formed in the CGGA sequence is due to different direct interactions of the enantiomeric non-leaving ligands with the protein. The affinity of the
Acknowledgments
This research was supported by the Grant Agency of the Czech Republic (Grant 305/05/2030), the Grant Agency of the Academy of Sciences of the Czech Republic (Grants A5004101 and S5004107). The authors also acknowledge that this work was also carried out within the Institutional Research Plan AVOZ50040507 “Biophysics of dynamic structures and functions of biological systems.”
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