DNA Interactions

In the field of electrochemical biosensing, transition metal complexes achieved a significant importance as hybridization indicators or electroactive markers of DNA. Their incorporation in electro-chemical DNA biosensors enables to offer a promising perspective in understanding of the biological activity of some chemical compounds. In this context, the development of innovative configurations of electrochemical DNA biosensors applied to life sciences during the last years were reviewed in the present article. In the first part, a brief introduction of nanomaterial based electrochemical DNA biosensors is given. In the second part, the complexes of transition metals with biological interest and their applications in electrochemical DNA biosensors are being described.

The photocytotoxicity of a series of anticancer trans-dihydroxido [Pt(N 3 ) 2 (OH) 2 (NH 3 )(X)] (X = alkyl or aryl amine) platinum(IV) diazido complexes has been examined and the influence of cistrans isomerism investigated. A series of photoactivatable Pt IV -azido complexes has been synthesized: the synthesis, characterisation and photocytotoxicity of six mixed-ligand ammine/ amine Pt IV diazido complexes, cis,trans,cis,-[Pt(N 3 ) 2 (OH) 2 (NH 3 )(X)] where X = propylamine (4c), butylamine (5c), pentylamine (6c) and aromatic complexes X= pyridine (7c) 2methylpyridine (8c), 3-methylpyridine (9c) are reported. Six all-trans isomers have also been studied where X = methylamine (2t), ethylamine (3t), 2-methylpyridine (8t), 4-methylpyridine (10t), 3-methylpyridine (9t) and 2-bromo-3-methylpyridine (11t). All the complexes exhibit intense azide-to-Pt IV LMCT bands (ca. 290 nm for trans and ca. 260 nm for cis). When irradiated with UVA light (365 nm) the Pt IV complexes undergo photoreduction to Pt II species, as monitored by UV-vis spectroscopy. The trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. One of the cis complexes (9c) was nonphotocytotoxic despite undergoing photoreduction. Substitution of NH 3 ligands by MeNH 2 or EtNH 2 results in more potent photocytotoxicity for the all-trans complexes. The complexes were all non-toxic towards human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark, apart from the 3-methylpyridine (9t) 2-bromo-3-methylpyridine (11t) and 4-methylpyridine (10t) derivatives.

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Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease (COPD). To determine the genetic underpinnings of lung function patterns in childhood asthmatics. We performed a genome-wide association study of 581 non-Hispanic white asthmatics that were previously classified by patterns of lung function growth and decline, (Normal Growth, Normal Growth with Early Decline, Reduced Growth, and Reduced Growth with Early Decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large COPD meta-analysis cohort. Interaction between the genomic region encompassing the most strongly associated single nucleotide polymorphism (SNP) and nearby genes was assessed by two chromosomal conformation capture assays. An intergenic SNP (rs4445257) on chromosome 8 was strongly as...

Curaxins and especially the second-generation derivative curaxin CBL0137 have important antitumor activities in multiple cancers such as glioblastoma, melanoma and others. Although most of the authors suggest that their mechanism of action comes from the activation of p53 and inactivation of NF-kB by targeting FACT, there is evidence supporting the involvement of DNA binding in their antitumor activity. In this work, the DNA binding properties of curaxin CBL0137 with model quadruplex DNA oligomers were studied by 1H NMR, CD, fluorescence and molecular modeling. We provided molecular details of the interaction of curaxin with two G-quadruplex structures, the single repeat of human telomere d(TTAGGGT)4 and the c-myc promoter Pu22 sequence. We also performed 1H and 31P NMR experiments were also performed in order to investigate the interaction with duplex DNA models. Our data support the hypothesis that the interaction of curaxin with G-quadruplex may provide a novel insight into the D...

A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production with dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 μM induces disintegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.

Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease (COPD). To determine the genetic underpinnings of lung function patterns in childhood asthmatics. We performed a genome-wide association study of 581 non-Hispanic white asthmatics that were previously classified by patterns of lung function growth and decline, (Normal Growth, Normal Growth with Early Decline, Reduced Growth, and Reduced Growth with Early Decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large COPD meta-analysis cohort. Interaction between the genomic region encompassing the most strongly associated single nucleotide polymorphism (SNP) and nearby genes was assessed by two chromosomal conformation capture assays. An intergenic SNP (rs4445257) on chromosome 8 was strongly as...

Curaxins and especially the second-generation derivative curaxin CBL0137 have important antitumor activities in multiple cancers such as glioblastoma, melanoma and others. Although most of the authors suggest that their mechanism of action comes from the activation of p53 and inactivation of NF-kB by targeting FACT, there is evidence supporting the involvement of DNA binding in their antitumor activity. In this work, the DNA binding properties of curaxin CBL0137 with model quadruplex DNA oligomers were studied by 1H NMR, CD, fluorescence and molecular modeling. We provided molecular details of the interaction of curaxin with two G-quadruplex structures, the single repeat of human telomere d(TTAGGGT)4 and the c-myc promoter Pu22 sequence. We also performed 1H and 31P NMR experiments were also performed in order to investigate the interaction with duplex DNA models. Our data support the hypothesis that the interaction of curaxin with G-quadruplex may provide a novel insight into the D...

The standard protocols for DNA analysis largely involve polymerase chain reaction (PCR). However, DNA structures bound to chemical agents cannot be PCR-amplified, and therefore any sequence changes induced by external agents may be neglected. Thus, the development of analytical tools capable of characterizing the biochemical mechanisms associated with chemically induced DNA damage is demanded for the rational design of more effective chemotherapy drugs, understanding the mode of actions of carcinogenic chemicals, and monitoring the genotypic toxicology of environments. Here we report a fast, high-throughput, low-cost method for the characterization and quantitative recognition of DNA interactions with exogenous agents based on surface-enhanced Raman scattering spectroscopy. As representative chemical agents, we selected a chemotherapeutic drug (cisplatin) which forms covalent adducts with DNA, a duplex intercalating agent (methylene blue), and a cytotoxic metal ion (Hg(II)) which in...

Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease (COPD). To determine the genetic underpinnings of lung function patterns in childhood asthmatics. We performed a genome-wide association study of 581 non-Hispanic white asthmatics that were previously classified by patterns of lung function growth and decline, (Normal Growth, Normal Growth with Early Decline, Reduced Growth, and Reduced Growth with Early Decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large COPD meta-analysis cohort. Interaction between the genomic region encompassing the most strongly associated single nucleotide polymorphism (SNP) and nearby genes was assessed by two chromosomal conformation capture assays. An intergenic SNP (rs4445257) on chromosome 8 was strongly as...

A series of ethylenediamine platinum(II) complexes connected through semi-rigid chains of 1,2-bis(4-pyridyl)ethane to DNA intercalating subunits (naphthalene, anthracene or phenazine) has been synthesized, and their interactions with calf thymus (CT) DNA have been evaluated by viscometric titrations and equilibrium dialysis experiments. The parent ligands that contain anthracene or phenazine chromophores showed a monointercalative mode of DNA interaction (especially the anthracene derivative), with apparent association constants in the order of 10 4 M-1. The corresponding platinum(II) complexes bind CT DNA through bisintercalation, as established by the significant increase of DNA contour length inferred from viscosity measurements, and the association constants are in the order of 10 5 M-1. The naphthalene derivatives, however, exhibit a mixed mode of interaction, which suggests a partial contribution of both intercalation and groove binding for the ligand, and monointercalation in the case of the platinum(II) complex. Competition dialysis experiments carried out on the intercalative compounds have revealed a moderate selectivity towards GC DNA sequences for the derivatives containing the anthracene chromophore.

A series of ethylenediamine platinum(II) complexes connected through semi-rigid chains of 1,2-bis(4-pyridyl)ethane to DNA intercalating subunits (naphthalene, anthracene or phenazine) has been synthesized, and their interactions with calf thymus (CT) DNA have been evaluated by viscometric titrations and equilibrium dialysis experiments. The parent ligands that contain anthracene or phenazine chromophores showed a monointercalative mode of DNA interaction (especially the anthracene derivative), with apparent association constants in the order of 10 4 M-1. The corresponding platinum(II) complexes bind CT DNA through bisintercalation, as established by the significant increase of DNA contour length inferred from viscosity measurements, and the association constants are in the order of 10 5 M-1. The naphthalene derivatives, however, exhibit a mixed mode of interaction, which suggests a partial contribution of both intercalation and groove binding for the ligand, and monointercalation in the case of the platinum(II) complex. Competition dialysis experiments carried out on the intercalative compounds have revealed a moderate selectivity towards GC DNA sequences for the derivatives containing the anthracene chromophore.

Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease (COPD). To determine the genetic underpinnings of lung function patterns in childhood asthmatics. We performed a genome-wide association study of 581 non-Hispanic white asthmatics that were previously classified by patterns of lung function growth and decline, (Normal Growth, Normal Growth with Early Decline, Reduced Growth, and Reduced Growth with Early Decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large COPD meta-analysis cohort. Interaction between the genomic region encompassing the most strongly associated single nucleotide polymorphism (SNP) and nearby genes was assessed by two chromosomal conformation capture assays. An intergenic SNP (rs4445257) on chromosome 8 was strongly as...

The world of drug designing is ever changing. The investigations of drug-DNA interactions would provide new compounds to be tested for an effect on a biochemical target, and also to be used as promising hybridization indicators for the design of DNA biosensors, which will further become DNA microchip systems. An overview is reported here about DNA biosensors based primarily on drugs interacting with DNA and shows how to determine this interaction electrochemically, the quantification of drug and/or DNA, and the promising applications of these drugs as DNA hybridization indicator. The applications of these electrochemical DNA biosensors are described and discussed.

The interaction of arsenic trioxide (As 2 O 3) with calf thymus double-stranded DNA (dsDNA), calf thymus singlestranded DNA (ssDNA) and also 17-mer short oligonucleotide (Probe A) was studied electrochemically by using differential pulse voltammetry (DPV) with carbon paste electrode (CPE) at the surface and also in solution. Potentiometric stripping analysis (PSA) was employed to monitor the interaction of As 2 O 3 with dsDNA in solution phase by using a renewable pencil graphite electrode (PGE). The changes in the experimental parameters such as the concentration of As 2 O 3 , and the accumulation time of As 2 O 3 were studied by using DPV; in addition, the reproducibility data for the interaction between DNA and As 2 O 3 was determined by using both electrochemical techniques. After the interaction of As 2 O 3 with dsDNA, the DPV signal of guanine was found to be decreasing when the accumulation time and the concentration of As 2 O 3 were increased. Similar DPV results were also found with ssDNA and oligonucleotide. PSA results observed at a low DNA concentration such as 1 ppm and a different working electrode such as PGE showed that there could be damage to guanine bases. The partition coefficients of As 2 O 3 after interaction with dsDNA and ssDNA in solution by using CPE were calculated. Similarly, the partition coefficients (PC) of As 2 O 3 after interaction with dsDNA in solution was also calculated by PSA at PGE. The features of this proposed method for the detection of DNA damage by As 2 O 3 are discussed and compared with those methods previously reported for the other type of DNA targeted agents in the literature.

Curaxins and especially the second-generation derivative curaxin CBL0137 have important antitumor activities in multiple cancers such as glioblastoma, melanoma and others. Although most of the authors suggest that their mechanism of action comes from the activation of p53 and inactivation of NF-kB by targeting FACT, there is evidence supporting the involvement of DNA binding in their antitumor activity. In this work, the DNA binding properties of curaxin CBL0137 with model quadruplex DNA oligomers were studied by 1H NMR, CD, fluorescence and molecular modeling. We provided molecular details of the interaction of curaxin with two G-quadruplex structures, the single repeat of human telomere d(TTAGGGT)4 and the c-myc promoter Pu22 sequence. We also performed 1H and 31P NMR experiments were also performed in order to investigate the interaction with duplex DNA models. Our data support the hypothesis that the interaction of curaxin with G-quadruplex may provide a novel insight into the D...

A series of ethylenediamine platinum(II) complexes connected through semi-rigid chains of 1,2-bis(4-pyridyl)ethane to DNA intercalating subunits (naphthalene, anthracene or phenazine) has been synthesized, and their interactions with calf thymus (CT) DNA have been evaluated by viscometric titrations and equilibrium dialysis experiments. The parent ligands that contain anthracene or phenazine chromophores showed a monointercalative mode of DNA interaction (especially the anthracene derivative), with apparent association constants in the order of 10 4 M-1. The corresponding platinum(II) complexes bind CT DNA through bisintercalation, as established by the significant increase of DNA contour length inferred from viscosity measurements, and the association constants are in the order of 10 5 M-1. The naphthalene derivatives, however, exhibit a mixed mode of interaction, which suggests a partial contribution of both intercalation and groove binding for the ligand, and monointercalation in the case of the platinum(II) complex. Competition dialysis experiments carried out on the intercalative compounds have revealed a moderate selectivity towards GC DNA sequences for the derivatives containing the anthracene chromophore.

A regulatory program involving hundreds of genes is coordinated by p53 to prevent carcinogenesis in response to stress. Given the importance of chromatin loops in gene regulation, we investigated whether DNA interactions participate in the p53 stress response. To shed light on this issue, we measured the binding dynamics of cohesin in response to stress. We reveal that cohesin is remodeled at specific loci during the stress response and that its binding within genes negatively correlates with transcription. At p53 target genes, stressinduced eviction of cohesin from gene bodies is concomitant to spatial reorganization of loci through the disruption of functional chromatin loops. These findings demonstrate that chromatin loops can be remodeled upon stress and contribute to the p53-driven stress response. Additionally, we also propose a mechanism whereby transcription-coupled eviction of cohesin from CDKN1A might act as a molecular switch to control spatial interactions between regulatory elements.

The biomolecular interactions of platinum derivatives widely used as anticancer drugs: cisdiamminedichloroplatinum(II) and oxaliplatin with calf thymus double-stranded DNA were studied using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) in combination with single-walled carbon nanotubes modified graphite electrode (SWCNTs-GE) and unmodified graphite electrode (bare GE). The performance of these biomolecular interactions were explored at the electrode surface by monitoring the changes at guanine oxidation signal in terms of optimum interaction times by comparing the results of SWCNTs-GE with bare one. The features of these electrochemical sensors based on carbon nanotubes for monitoring of biomolecular interactions were discussed and compared with the earlier conventional ones.

A regulatory program involving hundreds of genes is coordinated by p53 to prevent carcino-genesis in response to stress. Given the importance of chromatin loops in gene regulation, we investigated whether DNA interactions participate in the p53 stress response. To shed light on this issue, we measured the binding dynamics of cohesin in response to stress. We reveal that cohesin is remodeled at specific loci during the stress response and that its binding within genes negatively correlates with transcription. At p53 target genes, stress-induced eviction of cohesin from gene bodies is concomitant to spatial reorganization of loci through the disruption of functional chromatin loops. These findings demonstrate that chromatin loops can be remodeled upon stress and contribute to the p53-driven stress response. Additionally, we also propose a mechanism whereby transcription-coupled eviction of cohesin from CDKN1A might act as a molecular switch to control spatial interactions between regulatory elements.