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PubMed2003

Poly(ADPR) polymerase-1 and poly(ADPR) glycohydrolase level and distribution in differentiating rat germinal cells.

Poly(ADP-ribose)polymerase (PARP-1) and poly(ADP-ribose)glycohydrolase (PARG) are responsible for the transient poly(ADP-ribosyl)ation of proteins in eukaryotic cells. This biochemical reaction plays an active role in DNA replication and repair, transcription, cell differentiation and death. The aim of this study was to investigate the levels and the sub-cellular distribution of such enzymes in rat germinal cells at different stages of differentiation, i.e. in primary spermatocytes and round spermatids, representing meiotic and post-meiotic cells, respectively. The determination of the level of PARP-1 mRNA and protein revealed its higher expression in primary spermatocytes, thus implying that PARP-1 is one of the meiotic genes whose expression is requested at the pachytene phase of the meiosis. We also demonstrated that rat germinal cells contain both the forms of PARG (i.e. of 110 and 60 kDa) so far described in somatic cells. In our experimental system, the large PARG was present and active mainly in the nuclear fraction of primary spermatocytes, whereas round spermatids showed a higher level of the 60 kDa PARG in the post-nuclear fraction. Collectively, our data show a different expression level of PARP-1 and a different endocellular distribution of PARG and suggest a role for the poly(ADP-ribose) turnover in distinct pathways in meiotic and post-meiotic germinal cells.

Animals↗
PubMed1983

Conformational transitions in oriented fibres of the synthetic polynucleotide poly[d(AT)].poly[d(AT)] double helix.

The synthetic polynucleotide poly[d(AT)].poly[d(AT)] is of interest in studies of the relationship between nucleic acid structure and function. In particular, A + T-rich regions in DNA double helices have been invoked as centres for controlling the transcription of genetic information. Here we describe conditions for observing by X-ray fibre diffraction the A, B, C and D conformations of Na-poly[d(AT)].poly[d(AT)], and for inducing transitions between these conformations. The D form emerges as a particularly stable conformation; once assumed, it persists over a wide range of variation in the relative humidity of the fibre environment. Further, while transitions between the B and D conformations are readily reversible, transitions between A and D are much more complex.

Nucleic Acid Conformation↗
PubMed1983

Escherichia coli polymerase I can use O2-methyldeoxythymidine or O4-methyldeoxythymidine in place of deoxythymidine in primed poly(dA-dT).poly(dA-dT) synthesis.

O2-and O4-alkyldeoxythymidine are among the four O-alkyl base-modified derivatives produced by the reaction of N-nitroso alkylating agents with nucleic acids in vitro and in vivo. We find that both O2- and O4-methyl-dTTP can substitute for dTTP in alternating poly(dA-dT)-primed DNA synthesis. Up to 22% of the pyrimidines in the newly synthesized polymer were found by HPLC analysis to be O-methyldeoxythymidine. Little polymer synthesis was observed in the absence of dTTP. However, the O-methyl-dTTPs did not inhibit polymerization of dATP and dTTP. Polymers containing O2- or O4-methyldeoxythymidine were obtained in good yield, retaining the secondary structure of alternating poly(dA-dT). This was shown by the data for thermal transition under different conditions. In contrast, poly(dA-dT).poly(dA-dT) methylated or ethylated to less than 4% total modification by alkylnitrosoureas had a distinctly less stable structure. Neither O2- nor O4-methyldeoxythymidine can form more than one hydrogen bond with adenosine. The unchanged secondary structure of polymers containing these modified thymidines indicates that stacking interactions must play a major role in helix stabilization. O-Alkyldeoxythymidine may be formed by N-nitroso carcinogens that react intracellularly. We have shown that the triphosphates can be utilized by Escherichia coli DNA polymerase I as dTTP. The incorporated O4-methyl-dT causes misincorporation of G, both in transcription and synthesis. When O2-methyl-dT is present, less, but definite, misincorporation results.

DNA Polymerase I↗
PubMed1988

Characterization of the minor groove environment in a drug-DNA complex: bisbenzimide bound to the poly[d(AT)].poly[d(AT)]duplex.

We compare the fluorescence properties of bisbenzimide (also known as Hoechst 33258) bound to the minor groove of the poly[d(AT)].poly[d(AT)] duplex with the corresponding fluorescence properties of bisbenzimide dissolved in neat organic solvents and mixed organic/aqueous solvents. Based on these comparisons, we conclude that the minor groove of the bisbenzimide-poly[d(AT)].poly[d(AT)] complex is quite nonpolar and exhibits a local dielectric constant of approximately 20 D. We discuss how this insight influences our understanding of the molecular forces that dictate and control the binding affinities and specificities of minor groove-directed DNA binding ligands.

Benzimidazoles↗
PubMed2003

Identification of a human cytoplasmic poly(A) nuclease complex stimulated by poly(A)-binding protein.

The poly(A) tail shortening in mRNA, called deadenylation, is the first rate-limiting step in eukaryotic mRNA turnover, and the polyadenylate-binding protein (PABP) appears to be involved in the regulation of this step. However, the precise role of PABP remains largely unknown in higher eukaryotes. Here we identified and characterized a human PABP-dependent poly(A) nuclease (hPAN) complex consisting of catalytic hPan2 and regulatory hPan3 subunits. hPan2 has intrinsically a 3' to 5' exoribonuclease activity and requires Mg2+ for the enzyme activity. On the other hand, hPan3 interacts with PABP to simulate hPan2 nuclease activity. Interestingly, the hPAN nuclease complex has a higher substrate specificity to poly(A) RNA upon its association with PABP. Consistent with the roles of hPan2 and hPan3 in mRNA decay, the two subunits exhibit cytoplasmic co-localization. Thus, the human PAN complex is a poly(A)-specific exoribonuclease that is stimulated by PABP in the cytoplasm.

Amino Acid Sequence↗
PubMed1985

Untenability of the heteronomous DNA model for poly(dA).poly(dT) in solution. This DNA adopts a right-handed B-DNA duplex in which the two strands are conformationally equivalent. A 500 MHz NMR study using one dimensional NOE.

1D NOE 1H NMR spectroscopy at 500 MHz was employed to examine the structure of poly(dA).poly(dT) in solution. NOE experiments were conducted as a function of presaturation pulse length (50, 30, 20 and 10 msec) and power (19 and 20 db) to distinguish the primary NOEs from spin diffusion. The 10 msec NOE experiments took 49 hrs and over 55,000 scans for each case and the difference spectra were almost free from diffusion. The spin diffused NOE difference spectra as well as difference NOE spectra in 90% H2O + 10% D2O in which TNH3 was presaturated enabled to make a complete assignment of the base and sugar protons. It is shown that poly(dA).poly(dT) melts in a fashion in which single stranded bubbles are formed with increasing temperature.

DNA↗
PubMed1988

Monte-Carlo simulation of DNA duplex hydration. B and B' conformations of poly(dA).poly(dT) have different hydration shells.

Monte-Carlo simulation of poly(dA).poly(dT) hydration by 30 water molecules per nucleotide pair has been performed. Two B-family conformations, both with a 36 degrees helical twist but with different minor groove widths, were considered. One conformation is Arnott's standard B form, the other one is specific for poly(dA).poly(dT) B' form with a narrowed minor groove. The mean energies and the mean numbers of water-water and water-DNA hydrogen bonds are close for the two conformations. Nevertheless, the hydration shell of the B' form differs drastically from that of the standard B form. The water arrangement in the minor groove of the B' form resembles the spine of hydration in the central part of Dickerson's dodecamer d(CGCGAATTCGCG). No such spine is formed in the hydration shell of the usual B form with a wider minor groove. In this conformation water bridges between adenine N3 or thymine O2 and oxygen of the sugar ring of the neighbouring nucleotide along the chain can be formed ("strings" in Dickerson's decamer d(CCAAGATTGG].

DNA↗
PubMed1989

FTIR study of netropsin binding to poly d(A-T) and poly dA.poly dT.

Complexes between netropsin and two polynucleotides containing only AT base pairs (poly d(A-T) and poly dA.poly dT) have been prepared at various drug/base pair ratios and studied in solution by Fourier Transform Infrared Spectroscopy. The drug is shown to interact in the narrow groove of poly d(A-T) with the C2O2 carbonyl of thymines and the N3 groups of adenines. Moreover the spectral modifications allow us to propose the existence of interactions at the level of the deoxyribose. No effect is detected on the phosphate groups when netropsin is progressively added. In the case of poly dA.poly dT the interaction seems much weaker as if the high propeller twist of the homopolymer would make the accessibility of the drug to the minor groove more difficult.

Base Composition↗
PubMed1990

Conformational isomerizations of the poly(dA-dT) and poly(amino2dA-dT) duplexes involving the unusual X-DNA double helix: a fourth derivative spectrophotometric study.

Fourth derivative spectrophotometry has been applied to monitor conformational isomerizations of polynucleotides for the first time. The transitions studied have been the B-A and A-X isomerizations of poly(dA-dT) and the B-X one of poly(amino2dA-dT). Parameters obtained from the fourth derivative spectra have been used to follow these conformational changes. The A form of poly(dA-dT) has been characterized by a new fourth derivative peak at 293.0 nm which can be associated to interstrand adenine-adenine interactions. Furthermore, some of the fourth derivative peaks in the long wavelength region (270-310 nm) can be related to stacking interactions present in the polynucleotide double helices. The tentative assignment of these peaks, particularly that at 299.0 nm in the derivative spectra of poly(amino2dA-dT), to n----pi electronic transitions is discussed.

Isomerism↗
PubMed1992

Structure of poly d(A).poly d(T).

On the basis of the x-ray data from polycrystalline and well oriented fibers of the sodium salt of poly d(A).poly d(T) (Arnott et al, Nucl. Acids Res. 11, 4141-4155 (1983), a revised B'-DNA model incorporating B-like adenine and thymine strands is shown to give a much better x-ray agreement (R = 0.25) than the previously assigned model consisting of mixed sugar conformations in the two strands. The narrowing of the minor and the widening of the major grooves are promiscuous features of B'-DNA, which are common to all poly d(purine).poly d(pyrimidine) duplexes with two hydrogen bonded base-pairs and are in marked contrast with classical B-DNA. Due to modest propeller (-15 degrees), the cross strand diagonal hydrogen bonds (0.37 nm) in this duplex are not as strong as those in A,T-rich oligonucleotide crystal structures.

Base Composition↗
PubMed1995

Structures of poly(dG-dC) and poly(dA-dT) stabilized by anions.

Infrared spectra were used to show that the sodium salts of acetate, sulfate and phosphate (pH 7.2) selectively stabilize some of the alternative structures of poly(dG-dC).Na and poly(dA-dT).Na as a function of hydration in nonoriented gels. NaCl was used as a reference. Each anion was present at 0.36 mole per mole of nucleotide residue. The weak absorption bands from these anions did not interfere with conclusive interpretation of the IR spectra of the polynucleotides. Poly(dG-dC).Na assumed the usual B* structure with each of the anions at high hydrations (r.h. of the ambient air > or = 94%). Lowering the hydration gave the following results. With acetate, the B* structure remained with only a small fraction of a modified Z or some other unusual structure present. With sulfate or phosphate, a sharp transition to the Z structure occurred (essentially complete by 86% r.h.). With reference to chloride ions, acetate favors the B* while sulfate and phosphate (pH 7.2) favors the Z structure. Poly(dA-dT).Na assumed the usual B structure with each of the anions at high hydrations. Lowering the hydration gave the following results. With acetate, the A structure was observed at the same hydrations as with chloride. With sulfate, a sharper transition to the A structure occurred (complete by 80% r.h.). With phosphate, a still sharper transition to the A structure occurred (complete by 86% r.h.). With reference to chloride, acetate shows little difference but sulfate and phosphate (pH 7.2) promote the A over the B structure. These results are compared with past results for NaNO3.

Acetates↗
PubMed1992

Anti-human immunodeficiency virus effects of zidovudine in combination with double-stranded RNA poly I poly C in T cells and monocytes-macrophages.

A comparison of the activity against human immunodeficiency virus 1 of zidovudine (AZT) and poly I poly C double-stranded RNA both alone and in combination in MT4 cells and primary monocyte/macrophage (M/M) cultures was made. The inhibition of the HIV-induced cytopathic effect or reverse transcriptase production by AZT in MT4 cells was not modified by the combination of the two agents. In contrast, AZT inhibition of reverse transcriptase production in the supernatant of M/M cultures was enhanced by the addition of poly I poly C. The inhibitory effect of the drug combination was more marked in M/M than in MT4 cells, indicating that the evaluation of compounds involving the induction of an antiviral state should be tested not only CD4+ T cells but also in monocyte-macrophages.

Cell Line↗
PubMed1981

Prevention of varicella zoster (VZ) with poly(I) . poly(C) given during the incubation period.

Poly I . Poly C (Poly I:C) was administered to six children with cancer who were exposed to varicella zoster (VZ) and who were under active treatment to determine if this agent could prevent the development of overt varicella zoster (chickenpox). Poly I:C was administered as a single injection during the incubation period, but beyond 72 hours, since zoster immunoglobulin (ZIG) is a proven effective agent in the first 72 hours. None of these patients had a prior history of VZ and neither ZIG nor any other known antiviral agent was administered to these patients. None of the children developed chickenpox. This appears significant but awaits confirmation in a larger control study.

Antibodies, Viral↗
PubMed1982

Enhancement of interferon-mediated protein kinase in mouse and human plasma in response to treatment with polyadenylic-polyuridylic acid (poly A:poly U).

Interferon-treated mouse and human cells show enhanced levels of kinase activity manifested by the phosphorylation of endogenous 67,000 (p67K kinase) and 72,000 (p72K kinase) molecular weight proteins, respectively. Both the p67K kinase and the p72K activities are detectable in mouse and human plasma. We have previously shown that the p67K kinase in the plasma of mice may serve as a marker for the presence and action of interferon. Here we show that these kinase activities are enhanced in mice and in patients treated with polyadenylic-polyuridylic acid (Poly A:Poly U) at doses (0.4-0.6 mg/kg body weight) which do not lead to detectable amount of circulating interferon. Mice injected with higher doses of Poly A:Poly U (2-10 mg/kg body weight) show detectable levels of circulating interferon in addition to enhanced levels of p67K kinase in their plasma. Interferon produced under these conditions is acid stable.

Adenocarcinoma↗
PubMed1983

Response of L-1210 tumor in mice toward treatment with interferon or poly(I) X poly(C).

Two interferon (IFN)-mediated enzyme activities, the protein kinase and pppA(2'p5'A)n synthetase (2-5A synthetase) were employed to demonstrate the action of IFN on different tissues of mice as well as in ascitic tumors of L-1210 IFN (alpha + beta)-sensitive (L-1210S) and IFN-resistant (L-1210R) leukemia cells. The protein kinase is manifested by the phosphorylation of endogenous protein of molecular weight 67 kD (p67K kinase). Control and L-1210R or L-1210S tumor-bearing mice were found to respond similarly to treatment with IFN or when injected with an IFN inducer, poly(I) X poly(C). The 2-5A synthetase and the p67K kinase were enhanced in the lung and the spleen of mice, both control and with tumor graft. There was no apparent effect on L-1210R leukemia cells whereas in L-1210S cells the level of both enzymes was enhanced in response to treatment of mice with IFN or poly(I) X poly(C). These results indicate that the presence of tumor cells did not trigger modifications in the response of mice toward treatment with IFN. Furthermore, they provide biochemical evidences to show the response of IFN-sensitive and IFN-resistant tumor cells during treatment of the host with IFN.

2',5'-Oligoadenylate Synthetase↗
PubMed1983

Effect of poly I:C/poly-L-lysine (poly ICL) on the development of murine osteogenic sarcoma.

Poly I:C/poly-L-lysine (poly ICL) was effective in preventing or delaying the development of osteogenic sarcoma (OGS) in mice. C57BL/6J mice were inoculated subcutaneously with 5 X 10(4) OGS cells and treatment was evaluated by palpable tumor development and subsequent day of death. A significant antitumor effect resulted from injection of 150 microgram of poly ICL into the tumor site starting immediately after tumor implant and followed by four subsequent treatments. Seventy percent of treated animals remained tumor free at 50 days, a time at which 70% of placebo treated animals had died as a result of tumor development. A similar treatment regimen of mice inoculated with 2 X 10(5) OGS cells resulted in a significant delay of time to tumor and subsequent day of death. Treatments with poly ICL were ineffective if they were initiated after development of palpable tumor or if they were administered at a nontumorous site on the animal. These findings indicate that the optimal therapy resulted from repeated intratumor treatment prior to development of extensive tumor burden.

Animals↗
PubMed1988

Effect of interferons and poly(I):poly(C) on the pathogenesis of the diabetogenic variant of encephalomyocarditis virus in different mouse strains.

Interferon (IFN) can either prevent or exacerbate the pathogenic effects of the diabetogenic variant of encephalomyocarditis (EMC-D) virus. The effect seen is dependent upon the mouse strain and the time of IFN administration. For example, IFN-alpha beta protects SWR/J but not ICR Swiss male mice against the diabetogenic effects of the virus. Administration of either IFN-alpha beta or the IFN-inducer poly(I):poly(C) 4 days post infection, results in an exacerbation of the infection in ICR Swiss and C57BL/6 male mice. Studies have been initiated to investigate the role of the IFN system in the pathogenesis of this virus infection. In this study IFNs or poly(I):poly(C) were administered to several mouse strains at 24 h before or 4 days after infection with EMC-D virus. The results of such treatment ranged from complete protection of the animals from the diabetogenic effects of the virus to exacerbation of the infection as reflected by the virus content in selected organs. The effect was dependent upon the mouse strain, the type of IFN, and the time of its administration in relation to virus infection.

Animals↗
PubMed1982

The B reversible Z transition of poly(dI-br5dC).poly(dI-br5dC). A quantitative description of the Z form dynamic structure.

The study of poly(dI-br5dC).poly(dI-br5dC) films by infrared spectroscopy shows that in low salt concentration, the conformation of this polynucleotide belongs to the B-family and in high salt concentration to the Z-family. 31P nuclear magnetic resonance and circular dichroism confirm the existence of these two forms. By circular dichroism and ultraviolet absorption, it is shown that the equilibrium constant of the B reversible Z transition depends upon temperature. The deuteration rates of exchangeable protons involved in hydrogen bonds between base pairs were deduced from the changes in absorbance near 1700 cm-1. In the B-form, one class of protons is measured with an exchange half-time of 20 minutes. In the Z-form, two classes of protons are measured with very different exchange half-times, the exchange half-time of the slow protons being of the order of 850 minutes. By comparison of these results with those previously obtained for poly(dG-dC).poly(dG-dC), these very slow protons of these two Z-polynucleotides are identified as the cytosine amino protons. A quantitative description of the dynamic structure of the Z-form is presented.

Circular Dichroism↗