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PubMed2004

DNA modification in chick heart and cerebrum.

Heart muscle cells and cerebral neurons are known to lose the ability to proliferate and are called terminally differentiated cells. They are generated in appropriate numbers during embryogenesis and retained throughout adult life without turnover. We are interested in such a long-lived DNA. We isolated DNA from chick heart and cerebrum and compared it with DNA from other organs after incubation with DNase I. Single-strand breaks were assessed using a reaction system composed of DNA and Escherichia coli DNA polymerase. The DNA of both organs was relatively resistant to DNase I, and DNA modification occurred during embryogenesis. CIMS (chemical ionization mass spectrometry) indicated that the molecular mass of the deoxynucleoside of both DNAs was larger than that of the corresponding canonical deoxyribonucleoside by m/z 28 (or 30 for the protonated form). The difference between these deoxynucleosides is based on a difference in sugar constituents. Cerebral deoxynucleotides were analyzed by (13)C NMR. An extra signal near 173 ppm was observed, which was assigned to the amide carbonyl. We propose a model of the deoxynucleoside where a carbonyl residue exists between the base and the 2-deoxyribose moiety of the canonical deoxyribonucleoside.

Animals↗
PubMed2001

Fructose triggers DNA modification and damage in an Escherichia coli plasmid.

The nonenzymatic reaction between reducing sugars and amino groups of long-lived macromolecules results in an array of chemical modifications that may account for several physiological complications. The characteristics of the reaction are directly related to the type of the reducing sugars involved, whether aldoses or ketoses, phosphorylated or non-phosphorylated, and these in turn determine the consequences of the induced modifications. So far, most studies have been focused on the nonenzymatic reaction between glucose and proteins, while the reaction with fructose, a faster glycating agent, attracted only a minor attention. We have recently demonstrated that long-term fructose consumption induces age-related changes in collagen from skin and cortical bones faster than glucose. In the present study we provide evidence that fructose and its phosphate metabolites can modify DNA faster than glucose and its phosphate metabolites under in vitro conditions. Incubating the plasmid pBR322 with fructose and glucose phosphate metabolites induced DNA modifications and damage that were verified by gel electrophoresis and transformation capacity of the plasmid into an Escherichia coli host. The intensity of the tested sugars to modified and damage DNA after incubation for 15 days increased significantly in the following order: glucose 1-phosphate < glucose < glucose 6-phosphate < fructose 1-phosphate < fructose < fructose 6-phosphate. The data suggest that fructose should deserve more attention as a factor that may influence glycation and induce physiological complications.

Journal Article↗
PubMed2000

[The synthesis of a cobalt(II) tetracarboxyphthalocyanine- deoxyribooligonucleotide conjugate as a reagent for the directed DNA modification].

The cobalt(II) tetracarboxyphthalocyanine-deoxyribonucleotide pd(TCTTCCCA) conjugate was synthesized. The phthalocyanine N-succinimide ester prepared from phthalocyanine using DCC was mixed in DMF with an aqueous solution of the oligonucleotide bearing a 1,3-diaminopropane linker at the 5'-phosphate. The resulting conjugate was tested in the intraduplex reaction with target 14-mer and 22-mer oligonucleotides containing conjugate-complementary sequences. In the presence of O2 and a thiol (2-mercaptoethanol or DTT) as a coupled reducer or H2O2, sequence-specific DNA modification was observed that caused the cleavage of the target upon treatment with piperidine.

Animals↗
PubMed2002

DNA modifications by antitumor platinum and ruthenium compounds: their recognition and repair.

The development of metal-based antitumor drugs has been stimulated by the clinical success of cis-diamminedichloroplatinum(II) (cisplatin) and its analogs and by the clinical trials of other platinum and ruthenium complexes with activity against resistant tumors and reduced toxicity including orally available platinum drugs. Broadening the spectrum of antitumor drugs depends on understanding existing agents with a view toward developing new modes of attack. It is therefore of great interest to understand the details of molecular and biochemical mechanisms underlying the biological efficacy of platinum and other transition-metal compounds. There is a large body of experimental evidence that the success of platinum complexes in killing tumor cells results from their ability to form various types of covalent adducts on DNA; thus, the research of DNA interactions of metal-based antitumor drugs has predominated. The present review summarizes current knowledge on DNA modifications by platinum and ruthenium complexes, their recognition by specific proteins, and repair. It also provides strong support for the view that either platinum or ruthenium drugs, which bind to DNA in a fundamentally different manner from that of 'classical' cisplatin, have altered pharmacological properties. The present article also demonstrates that this concept has already led to the synthesis of several new unconventional platinum or ruthenium antitumor compounds that violate the original structure-activity relationships.

Amino Acid Sequence↗
PubMed2000

Characterization of the Ni(III) intermediate in the reaction of (1,4,8,11-tetraazacyclotetradecane)nickel(II) perchlorate with KHSO5: implications to the mechanism of oxidative DNA modification.

We report the detection and characterization of the Ni(III) intermediates generated by reaction of (1,4,8,11-tetraazacyclotetradecane)nickel(II) perchlorate with KHSO5. Four Ni(III) intermediates can be trapped or detected through variation in Cl- or KHSO5 concentrations. Upon oxidation of [Ni(cyclam)]2+ by 2.5 equiv of KHSO5, deprotonation of the cyclam ligand generates two red Ni(III) species with lambda max = 530 nm and g perpendicular = 2.20 and g parallel = 2.02 or g perpendicular = 2.16 and g parallel = 2.01 for the axial 4-coordinate or 6-coordinate dichloride species, respectively. These forms decay to Ni(II) products via complex ligand oxidation mechanisms. The Ni(III) dichloride species can be reprotonated and subsequently binds to DNA via an outer-sphere interaction as evidenced by the inverted sign of the CD signal near 400 nm. Cumulatively, the results indicate that the Ni(III) center is coordinately saturated under excess chloride conditions but is still able to interact with DNA substrates. This suggests alternative mechanistic pathways for DNA modification by reaction of [Ni(cyclam)]2+ with KHSO5 and possibly other Ni(II) complexes as well.

Circular Dichroism↗
PubMed2005

DNA methyltransferases and structural-functional specificity of eukaryotic DNA modification.

Properties of the main families of mammalian, plant, and fungal DNA methyltransferases are considered. Structural-functional specificity of eukaryotic genome sequences methylated by DNA methyltransferases is characterized. The total methylation of cytosine in DNA sequences is described, as well as its relation with RNA interference. Mechanisms of regulation of expression and modulation of DNA methyltransferase activity in the eukaryotic cell are discussed.

Animals↗
PubMed1999

DNA modifications by a novel bifunctional trinuclear platinum phase I anticancer agent.

The DNA-binding profile of a novel, trinuclear platinum Phase I clinical agent (BBR3464) is summarized. The structure of BBR3464 is best described as two trans-[PtCl(NH3)2] units linked by a tetra-amine [trans-Pt(NH3)2{H2N(CH2)6NH2}2]2+ unit. The +4 charge of BBR3464, the presence of at least two Pt coordination units capable of binding to DNA, and the consequences of such DNA binding are remarkable departures from the cisplatin structural paradigm. The chemical and biological features argue that the drug should be considered the first clinical representative of an entirely new structural class of DNA-modifying anticancer agents. The high charge on BBR3464 facilitates rapid binding to DNA with a t1/2 of approximately 40 min, significantly faster than the neutral cisplatin. The melting temperature of DNA adducted by BBR3464 increased at low ionic strength but decreased in high salt for the same rb. This unusual behavior is in contrast to that of cisplatin. BBR3464 produces an unwinding angle of 14 degrees in negatively supercoiled pSP73 plasmid DNA, indicative of bifunctional DNA binding. Quantitation of interstrand DNA-DNA cross-linking in plasmid pSP73 DNA linearized by EcoRI indicated approximately 20% of the DNA to be interstrand cross-linked. While this is significantly higher than the value for cisplatin, it is, interestingly, lower than that for dinuclear platinum compounds such as [{trans-PtCl(NH3)2}2H2N(CH2)6NH2]2+ (BBR3005) where interstrand cross-linking efficiency may be as high as 70-90%. Either the presence of charge in the linker backbone or the increased distance between platinating moieties may contribute to this relatively decreased ability of BBR3464 to induce DNA interstrand cross-linking. Fluorescence experiments with ethidium bromide were consistent with the formation of long-range delocalized lesions on DNA produced by BBR3464. The sequence preference for BBR3464 on plasmid DNA was determined to the exact base pair by assaying extension of the polynucleotide by VentR(exo+) DNA polymerase. Strong sequence preference for single dG or d(GG) sites was suggested. The presence of relatively few blocks on DNA in comparison to either cisplatin or BBR3005 was indicative of high sequence selectivity. The following appropriate sequence where stop sites occur was chosen: [sequence: see text] molecular modeling on 1,4 interstrand (G'30 to G33) and 1,5 intrastrand (G33 to G29) cross-links further confirmed the similarity in energy between the two forms of cross-link. Finally, immunochemical analysis confirmed the unique nature of the DNA adducts formed by BBR3464. This analysis showed that antibodies raised to cisplatin-adducted DNA did not recognize DNA modified by BBR3464. In contrast, DNA modified by BBR3464 inhibited the binding of antibodies raised to transplatin-adducted DNA. Thus, the bifunctional binding of BBR3464 contains few similarities to that of cisplatin but may have a subset of adducts recognized as being similar to the transplatinum species. In summary, the results point to a unique profile of DNA binding for BBR3464, strengthening the original hypothesis that modification of DNA binding in manners distinct from that of cisplatin will also lead to a distinct and unique profile of antitumor activity.

Antineoplastic Agents↗
PubMed1998

[Interaction of derivatives of short oligonucleotides with nucleic acids. VIII. Characteristics of target DNA modification by alkylating oligonucleotide derivatives in tandem complexes].

The influence of effectors [octanucleotides and their 3',5'-di-N-(2-hydroxyethyl)phenazinium derivatives] on the modification of a target DNA by alkylating oligonucleotide derivatives forming duplexes of different stability with the target ws studied. It is shown that, being in tandem complexes immediately adjacent to the reactive group of an oligonucleotide reagent possessing a high hybridization capacity, the effector, on the one hand, enhances the stability of the reagent target duplex, and on the other hand, changes the site-specificity of alkylation and decreases the efficiency of the target modification at temperatures that provide a high extent of the target association with the reagent. Conversely, in the case of oligonucleotide reagents forming weak complexes with the target, effectors enhance both the stability of the target.reagent duplex and the extent of the target throughout the temperature range tested. The data indicate that the varying influence of effectors on the target modification by reagents with different hybridization capacities is due to conformational features of the target reagent duplexed regions. Increasing the rigidity of the target.reagent duplex reduces the efficiency of the target modification in tandem complexes.

Alkylating Agents↗
PubMed1990

Association between diet and age-related DNA modifications (I-compounds) in rat liver and kidney.

Mammalian tissue DNA has recently been found, by 32P-postlabeling, to contain complex profiles of age-dependent and tissue-specific bulky carcinogen adduct-like modifications, which have been termed I-compounds since they appeared to arise indigenously, in the absence of exposure to exogenous carcinogens. I-compounds are presumably formed by reaction of metabolically produced, as yet unidentified, electrophiles with DNA. In order to shed light on the origin of I-compounds, we have examined whether diet affects the levels and profiles of I-compounds. Weanling female Sprague-Dawley rats were provided with either one of three natural ingredient diets (rodent chows) or a purified diet (AIN-76A) for up to 6 months. Liver and kidney DNAs were analyzed after 0, 3, and 6 months of feeding, by a nuclease P1-enhanced 32P-postlabeling assay. Rats fed natural ingredient diets showed a greater complexity and 2.5-6.4-fold higher levels of I-compounds in the DNA of both tissues than rats fed purified diet. In addition, less marked qualitative and quantitative differences were noted among rats fed different chow diets. Three classes of I-compounds were identified: class A, I-spots common to both kinds of diet; class B, chow-specific spots; and class C, AIN-76A-specific spots. Liver and kidney shared some I-compounds, mostly belonging to class A, but there were also tissue-specific spots. These observations indicate a novel intimate link between diet and DNA modifications and are consistent with the hypothesis that the formation of I-compounds proceeds via normal metabolism of nutrients and other natural dietary components, leading to the production of small amounts of DNA-reactive electrophiles. Because of their DNA adduct-like character, I-compounds may play a critical role at the interface between nutrition and cancer.

Aging↗
PubMed1989

In vitro DNA modification by the ultimate carcinogen of 4-nitroquinoline-1-oxide: influence of superhelicity.

The effect of DNA tertiary structure on in vitro modification by 4-acetoxy-aminoquinoline-1-oxide (Ac-4-HAQO) was investigated. The reactivity of pAT153 plasmid DNA depended on the conformational state of the molecule: it progressively decreased according to the decrease of the superhelical tension, being negatively supercoiled DNA about two times more susceptible than singly-nicked relaxed DNA. HPLC of the three main Ac-4-HAQO adducts showed that 3-(deoxyguanosin-N2-yl)-4-aminoquinoline-1-oxide, N-(deoxyguanosin-C8-yl)-4-aminoquinoline-1-oxide and 3-(deoxyadenosin-N6-yl)-4-aminoquinoline-1-oxide accounted for 50, 25 and 10% of total quinoline DNA base adducts in all DNA conformations tested, except in the negatively supercoiled topoisomers where they accounted for 80, 15 and 5% respectively. DNA modification by Ac-4-HAQO resulted also in the formation of apurinic/apyrimidinic sites and in strand scissions. The quantification of these damages revealed that they represent an important fraction of all damaging events and that their yield is also influenced by DNA superstructure. Thus, these lesions must be considered as important DNA damage induced by Ac-4-HAQO.

4-Nitroquinoline-1-oxide↗
PubMed1996

Tyrosinase enhances the covalent modification of DNA by dopamine.

Dopamine-induced DNA damage was studied in vitro in the presence of the enzyme tyrosinase. Dopamine auto-oxidizes to form dopamine quinone, a reactive molecule which spontaneously decomposes to form additional reactive species that can modify cellular macromolecules. The conversion of dopamine to reactive dopamine quinone is accelerated by the enzyme tyrosinase. The objective of this study was to evaluate whether dopamine autoxidation would lead to DNA-reactive intermediates and whether tyrosinase would increase the rate of this reaction. Incubation of DNA with [3H]dopamine resulted in the concentration-dependent covalent incorporation of the labeled catecholamine into precipitable nucleic acid (DNA adduct formation). The presence of tyrosinase increased the incorporation by as much as two orders of magnitude. Antioxidants markedly reduced this incorporation, suggesting that dopamine free-radicals were critical in DNA modification. DNA adducts formed by dopamine in the presence of tyrosinase were visualized using 32P-postlabeling and thin layer chromatography. The results suggest that DNA modification by dopamine is accelerated by tyrosinase which, in turn, could contribute to destruction of dopaminergic neurons in vivo.

Antioxidants↗
PubMed1995

DNA modification by methyltransferases.

Enzymatic methylation of DNA plays important roles in both prokaryotes and eukaryotes. Structural study of the HhaI DNA methyltransferase has provided considerable insight into the chemistry of C5-cytosine methylation. The DNA-protein complex reveals a substrate cytosine flipped out of the double helix during the reaction, and a novel two-loop DNA-binding motif used for both sequence recognition and flipping the base. Structural comparison of HhaI C5-cytosine methyltransferase, TaqI N6-adenine methyltransferase, and catechol O-methyltransferase reveals a common catalytic domain structure, which might be universal among S-adenosyl-L-methionine (SAM)-dependent methyltransferases.

Amino Acid Sequence↗