GG sequence of DNA and the human telomeric sequence react with cis-diammine-diaquaplatinum at comparable rates

Ourliac‐Garnier, Isabelle; Bombard, Sophie

doi:10.1016/j.jinorgbio.2006.11.005

Cited by 23 publications

(19 citation statements)

References 39 publications

(53 reference statements)

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“…[69] All previous competition studies have been conducted under the kinetic control of N7-Pt II binding or N7 methylation. [44][45][46] In contrast to the labor-intensive analytical methods needed to assess sites of N7 platination and methylation, changes in 2PyG fluorescence provide a highly convenient and direct readout of metal-binding interactions at defined sites. The unusual fluorescence properties of 2PyG also provide a photophysical handle for studies aimed at characterizing electron and energy transfer in nucleic acids.…”

Section: Resultsmentioning

confidence: 99%

“…N7 positions are well solvated and available for metal binding in duplex DNA, [1,3,13,15] but G-quadruplex and triplex structures utilize N7 hydrogen bonding for stabilization (Scheme 1). Previous studies have demonstrated that G-tetrad formation in quadruplexes can compete with Pt II binding at N7, [44][45][46] but these reactions are under kinetic control and result in complex product mixtures. We were therefore interested in developing C8-modified purines for site-specific control of metalbinding interactions in diverse applications, such as the Abstract: A synthetic strategy that utilizes O6-protected 8-bromoguanosine gives broad access to C8-guanine derivatives with phenyl, pyridine, thiophene, and furan substituents.…”

Section: Introductionmentioning

confidence: 99%

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Site‐Specific Control of N7–Metal Coordination in DNA by a Fluorescent Purine Derivative

Dumas

Luedtke

2011

Chemistry A European J

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A synthetic strategy that utilizes O6-protected 8-bromoguanosine gives broad access to C8-guanine derivatives with phenyl, pyridine, thiophene, and furan substituents. The resulting 8-substituted 2'-deoxyguanosines are push-pull fluorophores that can exhibit environmentally sensitive quantum yields (Φ=0.001-0.72) due to excited-state proton-transfer reactions with bulk solvent. Changes in nucleoside fluorescence were used to characterize metal-binding affinity and specificity of 8-substituted 2'-deoxyguanosines. One derivative, 8-(2-pyridyl)-2'-deoxyguanosine (2PyG), exhibits selective binding of Cu(II), Ni(II), Cd(II), and Zn(II) through a bidentate effect provided by the N7 position of guanine and the 2-pyridyl nitrogen atom. Upon incorporation into DNA, 2-pyridine-modified guanine residues selectively bind to Cu(II) and Ni(II) with equilibrium dissociation constants (K(d)) that range from 25 to 850 nM; the affinities depend on the folded state of the oligonucleotide (duplex>G-quadruplex) as well as the identity of the metal ion (Cu>Ni≫Cd). These binding affinities are approximately 10 to 1 000 times higher than for unmodified metal binding sites in DNA, thereby providing site-specific control of metal localization in alternatively folded nucleic acids. Temperature-dependent circular-dichroism studies reveal metal-dependent stabilization of duplexes, but destabilization of G-quadruplex structures upon adding Cu(II) to 2PyG-modified oligonucleotides. These results demonstrate how the addition of a single pyridine group to the C8 position of guanine provides a powerful new tool for studying the effects of N7 metalation on the structure, stability, and electronic properties of nucleic acids.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Site‐Specific Control of N7–Metal Coordination in DNA by a Fluorescent Purine Derivative

Dumas

Luedtke

2011

Chemistry A European J

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“…The human quadruplexes of telomeric sequences have therefore received attention in the context of the telomerase inhibition as a potential anti‐cancer therapy, using specific small molecules that are able to stabilize DNA quadruplexes [6,13]. Platinum complexes, which are widely used for cancer therapies, have a high affinity to attack N7 of the guanine residue [20,22]. However, N7 nitrogen is associated with the hydrogen bond stabilization of the G‐tetrad.…”

Section: Discussionmentioning

confidence: 99%

“…The formation of interstrand crosslinks requires partial disruption of the Watson–Crick base pairing within double strand DNA, and the cross‐linking reaction could therefore be expected to be rather slow. However, by contrast, kinetic measurements indicate that interstrand cross‐linking is as fast as intrastrand cross‐linking, or even faster [22]. However, the four guanines of a G‐quartet have their N7 atoms involved in hydrogen bonding.…”

mentioning

confidence: 99%

“…The influence of platination on the telomeric sequences was described previously by Garnier et al. [22], but the effect of platination on the quadruplex formation has never been described in detail. Guanine‐guanine cross‐linking by platinum atoms either welds together contiguous guanine residues and stabilizes the G‐quadruplex or the occupancy of N7 hydrogen bonds destabilizes these structural motifs.…”

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confidence: 99%

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Platination of telomeric sequences and nuclease hypersensitive elements of human c‐myc and PDGF‐A promoters and their ability to form G‐quadruplexes

Víglaský¹

2008

The FEBS Journal

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G-rich regions appear in several locations in the human genome, including at the ends of linear chromomes, the immunoglobin switch region, centromeres, fragile X syndrome repeats, and promoters of some genes [1]. The sequences repeated in tandem, with three or four adjacent guanines, have been known to form polymorphic quadruplexes containing G-quartets stabilized by cyclic Hoogsteen hydrogen bondings. Quadruplex structures are highly stable DNA or RNA structures formed on G-rich sequences [2]. The Na + and K + ions stabilize the stacking through their interactions with carbonyl oxygens of the eight guanines of two adjacent quartets [3]. Direct evidence for the presence of G-quadruplex structures in vivo has been reported both at the telomeres of the ciliate Stylonychia [4] and those of humans [5], and at the promoter of c-myc [6,7]. Moreover, other genomic regions were shown to be able to adopt quadruplex structures, such as the promoters of c-kit oncogene [6], HIF-1a [9], Bcl2 [10] and vascular endothelial growth factor [11].The stabilization of the G-quadruplex structure by small molecules is currently emerging as a very promising anti-cancer strategy. Therefore, molecules that stabilize G-quadruplex structures can be used as potential anti-cancer agents [12]. Indeed, recent studies strongly suggest that molecules able to stabilize the quadruplex structure of DNA can lead to an arrest of the proliferation of cancer cells [5,[12][13][14]. At each division of somatic cells, telomeres are shortened, a process leading to senescence and death. It has been shown in vitro that G-quadruplex structures of the human sequence (G 3 T 2 A) 3 G 3 formed in the presence of molecules stabilizing the G-quartet stacks, similar to anthraquinones or porphyrins, inhibit the activity of telomerase [13][14][15][16][17].The anti-tumor drug cisplatin (cis-[PtCl2(NH3)2]), known for its high affinity for G-rich sequences, was Naturally occurring G-rich DNA sequences that are able to form G-quadruplex structures appear as potential targets for anti-cancer chemotherapy, and therefore play an important role in cellular processes, such as cell aging, death and carcinogenesis. The telomeric regions of DNA and nuclease hypersensitive elements of human c-myc and PDGF-A promoters represent a very appealing target for cisplatin and may interfere with normal DNA function. Platinum complexes bind covalently to nucleobases, and especially to the N7 atom of guanines, and the four guanines of a G-quartet have their N7 atoms involved in hydrogen bonding. Therefore, within a G-quadruplex structure, only the guanines out of the stack of G-quartets should react with electrophilic species such as platinum (II) complexes. Platinum complexes have significant influence on the formation of G-quadruplexes. Results obtained by CD spectroscopy and temperature gradientgel electrophoresis clearly demonstrate that DNA platination significantly affects G-quadruplex folding for telomeric sequences; the abundance of un ⁄ misfolded DNAs compared to the G-quadruplex is...

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Tandem mass spectrometry of platinated quadruplex DNA

2011

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Quadruplexes are higher-order structures formed by G-rich DNA strands that are involved in various processes of cell cycle regulation, such as control of telomere length and participation in gene regulation. Because of these central biological functions, quadruplex DNA represents a promising target for cancer therapy, e.g. by applying organometallic drugs, such as cisplatin. High-resolution electrospray tandem mass spectrometry is evaluated as a technique for exploring structural features of unplatinated and platinated quadruplexes. Results of experiments on tetramolecular, bimolecular and monomolecular quadruplexes provide information about the extent of platination and the binding sites of the drug. The dissociation behavior of the different types of quadruplexes is compared. Tetramolecular quadruplexes were found to weave out a strand end in order to provide a platination site, and their fragmentation is characterized by the release of an unplatinated strand and the formation of a platinated triplex. Partial opening of the structure in combination with the loss of small fragments leads to truncated quadruplex ions. For the bimolecular quadruplexes studied, strand separation is the predominant dissociation pathway. Depending on the loop sequence, cross-linking of the loops by cisplatin is demonstrated. Distinct differences in the product ion spectra of unannealed and annealed monomolecular sequences provide proof of quadruplex formation and show that platination preferentially occurs at the terminal regions.

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GG sequence of DNA and the human telomeric sequence react with cis-diammine-diaquaplatinum at comparable rates

Cited by 23 publications

References 39 publications

Site‐Specific Control of N7–Metal Coordination in DNA by a Fluorescent Purine Derivative

Site‐Specific Control of N7–Metal Coordination in DNA by a Fluorescent Purine Derivative

Platination of telomeric sequences and nuclease hypersensitive elements of human c‐myc and PDGF‐A promoters and their ability to form G‐quadruplexes

Tandem mass spectrometry of platinated quadruplex DNA

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