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See detailDNA interaction properties and topoisomerase I poisoning efficiencies of a new series of aza-indolocarbazole derivatives
Peixoto, Paul ULg; Hildebrand, Marie Paule; Baldeyrou, Brigitte et al

Poster (2006, June 02)

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See detailThe DNA intercalating alkaloid cryptolepine interferes with topoisomerase II and inhibits primarily DNA synthesis in B16 melanoma cells.
Bonjean, K.; De Pauw-Gillet, Marie-Claire ULg; Defresne, Marie-Paule ULg et al

in Biochemistry (1998), 37(15), 5136-46

Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host-mediated biological activities, including ... [more ▼]

Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host-mediated biological activities, including antibacterial, antiviral, and antimalarial properties. To date, the molecular basis for its diverse biological effects remains largely uncertain. Several lines of evidence strongly suggest that DNA might correspond to its principal cellular target. Consequently, we studied the strength and mode of binding to DNA of cryptolepine by means of absorption, fluorescence, circular, and linear dichroism, as well as by a relaxation assay using DNA topoisomerases. The results of various optical and gel electrophoresis techniques converge to reveal that the alkaloid binds tightly to DNA and behaves as a typical intercalating agent. In DNAase I footprinting experiments it was found that the drug interacts preferentially with GC-rich sequences and discriminates against homo-oligomeric runs of A and T. This study has also led to the discovery that cryptolepine is a potent topoisomerase II inhibitor and a promising antitumor agent. It stabilizes topoisomerase II-DNA covalent complexes and stimulates the cutting of DNA at a subset of preexisting topoisomerase II cleavage sites. Taking advantage of the fluorescence of the indoloquinoline chromophore, fluorescence microscopy was used to map cellular uptake of the drug. Cryptolepine easily crosses the cell membranes and accumulates selectively into the nuclei rather than in the cytoplasm of B16 melanoma cells. Quantitative analyses of DNA in cells after Feulgen reaction and image cytometry reveal that the drug blocks the cell cycle in G2/M phases. It is also shown that the alkaloid is more potent at inhibiting DNA synthesis rather than RNA and protein synthesis. Altogether, the results provide direct evidence that DNA is the primary target of cryptolepine and suggest that this alkaloid is a valid candidate for the development of tumor active compounds. [less ▲]

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See detailDNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid cryptolepine
Bailly, Christian; Laine, W.; Baldeyrou, B. et al

in Anti-Cancer Drug Design (2000), 15(3), 191-201

Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic ... [more ▼]

Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells. We have recently shown that cryptolepine can intercalate into DNA and stimulates DNA cleavage by human topoisomerase II. In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orientation of the indole unit with respect to the quinoline moiety. The biochemical and physicochemical results presented here indicate that neocryptolepine also intercalates into DNA, preferentially at GC-rich sequences, but exhibits a reduced affinity for DNA compared with cryptolepine. The two alkaloids interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer. The data provide a molecular basis to account for the reduced cytotoxicity of neocryptolepine compared with the parent drug. [less ▲]

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See detailDNA metabolism and development of organelles in guinea-pig megakaryocytes: a combined ultrastructural, autoradiographic and cytophotometric study
Paulus, Jean-Michel ULg

in Blood Blood (1970), 35(3), 298-311

The thick and thin section technique was used to combine ultrastructural studies of guinea-pig megakaryocytes with either autoradiographic studies of thymidine incorporation into megakaryoblast DNA or ... [more ▼]

The thick and thin section technique was used to combine ultrastructural studies of guinea-pig megakaryocytes with either autoradiographic studies of thymidine incorporation into megakaryoblast DNA or cytophotometric determination of megakaryocyte ploidy. Megakaryocytes engaged in polyploidization already showed granule and some demarcation membrane formation. The polyploidization phase stopped at the 8N, 16N, or 32N level after 3 plus or minus 0.5 (1 SD) genome duplications. [less ▲]

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See detailDNA methylation and cancer diagnosis: new methods and applications.
Dehan, Pierre ULg; Kustermans, Gaëlle ULg; Guénin, Samuel ULg et al

in Expert Review of Molecular Diagnostics (2009), 9(7), 651-7

Methylation of cytosines in cytosine-guanine (CpG) dinucleotides is one of the most important epigenetic alterations in animals. The presence of methylcytosine in the promoter of specific genes has ... [more ▼]

Methylation of cytosines in cytosine-guanine (CpG) dinucleotides is one of the most important epigenetic alterations in animals. The presence of methylcytosine in the promoter of specific genes has profound consequences on local chromatin structure and on the regulation of gene expression. Changes in DNA methylation play a central role in carcinogenesis. Hypermethylation and consecutive transcriptional silencing of tumor-suppressor genes has been documented in numerous cancers. The identification of target genes silenced by this modification has a great impact on diagnosis, classification, definition of risk groups and prognosis of cancer patients. Here we outline genome-wide techniques aiming at the identification of relevant methylated promoters. Methods and applications allowing clinicians to monitor the methylation of target genes will be also reviewed. [less ▲]

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See detailDNA methylation and expression of prolactin and growth hormone genes in a rat pituitary strain selected on steroid-depleted medium
Laverriere, J. N.; Muller, Marc ULg; Tougard, C. et al

in MacLeod, R. M.; Thorner, M. O.; Scapagnini, U. (Eds.) Prolactin, basic and clinical correlates (1985)

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See detailDNA methyltransferase DNMT3b protein overexpression as a prognostic factor in patients with diffuse large B-cell lymphomas
Amara, Khaled; Ziadi, Sonia; Hachana, Mohamed Ridha ULg et al

in Cancer Science (2010), 101(7), 1722-1730

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See detailDNA polymorphism detection in Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae): potential use in stored product pest management
Braet, Yves; Haubruge, Eric ULg

in DNA Sequence : The Journal of DNA Sequencing & Mapping (1995), 6

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See detailDNA promoter hypermethylation of BLU gene in invasive breast ductal carcinoma in Tunisia
Hachana, Mohamed Ridha ULg; Trimeche, Mounir; Amara, Khaled et al

in Virchows Archiv : An International Journal of Pathology (2007)

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See detailDNA released from dying host cells mediates aluminum adjuvant activity
Marichal, Thomas ULg; Ohata, Keiichi; Bedoret, Denis et al

in Nature Medicine (2011), 17

Aluminum-based adjuvants (alum) are widely used in human vaccination, although little is understood of their mechanisms of action. Here, we report that, in mice, alum causes the release of host cell DNA ... [more ▼]

Aluminum-based adjuvants (alum) are widely used in human vaccination, although little is understood of their mechanisms of action. Here, we report that, in mice, alum causes the release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production upon alum immunization. Indeed, we support that host DNA induces primary B cell responses, including IgG1 production, through Interferon Response Factor (Irf) 3-independent mechanisms, and 'canonical' type 2 T cell responses associated with IgE isotype switching and peripheral effector responses through Irf3-dependent mechanisms. The finding that host cell DNA is a damage-associated molecular pattern relaying alum adjuvant activity may thus help in the comprehension of the mechanisms of action of current vaccines and in the design of novel adjuvants. [less ▲]

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See detailDNA repair mechanisms: implication in cancer
Habraken, Yvette ULg

Post doctoral thesis (1999)

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See detailDNA replication timing data corroborate in silico human replication origin predictions
Audit, B.; Nicolay, Samuel ULg; Huvet, M. et al

in Physical Review Letters (2007), 99

We develop a wavelet-based multiscale pattern recognition methodology to disentangle the replication- from the transcription-associated compositional strand asymmetries observed in the human genome ... [more ▼]

We develop a wavelet-based multiscale pattern recognition methodology to disentangle the replication- from the transcription-associated compositional strand asymmetries observed in the human genome. Comparing replication skew profiles to recent high-resolution replication timing data reveals that most of the putative replication origins that border the so-identified replication domains are replicated earlier than their surroundings whereas the central regions replicate late in the S phase. We discuss the implications of this first experimental confirmation of these replication origin predictions that are likely to be early replicating and active in most tissues. [less ▲]

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See detailDNA sequences coding for the F18 fimbriae and AIDA adhesin are localized on the same plasmid in Escherichia coli isolates from piglets
Mainil, Jacques ULg; Jacquemin, E.; Pohl, P. et al

in Veterinary Microbiology (2002), 86

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See detailDNA vaccination for the priming of neutralizing antibodies against non-immunogenic STa enterotoxin from enterotoxigenic Escherichia coli
Ruth, Nadia ULg; Mainil, Jacques ULg; Roupie, Virginie et al

in Vaccine (2005), 23(27), 3618-3627

In order to test the use of DNA vaccination for its capacity to induce antibodies against the non-immunogenic heat-stable enterotoxin STa from Escherichia coli, BALB/c mice were immunized with plasmid DNA ... [more ▼]

In order to test the use of DNA vaccination for its capacity to induce antibodies against the non-immunogenic heat-stable enterotoxin STa from Escherichia coli, BALB/c mice were immunized with plasmid DNA encoding hybrid proteins made by the insertion of wild type STa or insertion of the Cys6Ala, Cys17Ala and Cys6Ala-Cys17Ala STa mutants at positions 195 or 216 of the TEM-1 beta-lactamase. No STa specific antibodies could be detected after three plasmid injections, but a subsequent boost with native STa peptide was capable of inducing low levels of neutralizing antibodies, as tested in the suckling mouse assay. Highest STa specific responses were found in mice primed with the double mutated STa inserted in position 195. This plasmid induced highest T-cell responses to the TEM-1 protein, indicating that priming of helper T-cell responses to the carrier protein was essential. Mixed IgG1/IgG2a isotypes also reflected this T helper 1 type priming. Moreover, insertion into loop A of the TEM-1 carrier may be more suitable than insertion into loop B, because of reduced competition between carrier and hapten B cell responses. [less ▲]

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See detailDNA-binding mechanism of the Escherichia coli Ada O(6)-alkylguanine-DNA alkyltransferase.
Verdemato, P. E.; Brannigan, J. A.; Damblon, Christian ULg et al

in Nucleic Acids Research (2000), 28(19), 3710-8

The C-terminal domain of the Escherichia coli Ada protein (Ada-C) aids in the maintenance of genomic integrity by efficiently repairing pre-mutagenic O:(6)-alkylguanine lesions in DNA. Structural and ... [more ▼]

The C-terminal domain of the Escherichia coli Ada protein (Ada-C) aids in the maintenance of genomic integrity by efficiently repairing pre-mutagenic O:(6)-alkylguanine lesions in DNA. Structural and thermodynamic studies were carried out to obtain a model of the DNA-binding process. Nuclear magnetic resonance (NMR) studies map the DNA-binding site to helix 5, and a loop region (residues 151-160) which form the recognition helix and the 'wing' of a helix-turn-wing motif, respectively. The NMR data also suggest the absence of a large conformational change in the protein upon binding to DNA. Hence, an O:(6)-methylguanine (O:(6)meG) lesion would be inaccessible to active site nucleophile Cys146 if the modified base remained stacked within the DNA duplex. The experimentally determined DNA-binding face of Ada-C was used in combination with homology modelling, based on the catabolite activator protein, and the accepted base-flipping mechanism, to construct a model of how Ada-C binds to DNA in a productive manner. To complement the structural studies, thermodynamic data were obtained which demonstrate that binding to unmethylated DNA was entropically driven, whilst the demethylation reaction provoked an exothermic heat change. Methylation of Cys146 leads to a loss of structural integrity of the DNA-binding subdomain. [less ▲]

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See detailDNase I hypersensitive sites far upstream of the rat tryptophan oxygenase gene direct developmentally regulated transcription in livers of transgenic mice.
Kaltschmidt, Christian; Muller, Marc ULg; Brem, Gottfried et al

in Mechanisms of Development (1994), 45(3), 203-10

Expression of the gene coding for tryptophan oxygenase (TO) is switched on in rat liver about two weeks after birth. We identified two clusters of DNaseI hypersensitive (HS) sites in the TO gene upstream ... [more ▼]

Expression of the gene coding for tryptophan oxygenase (TO) is switched on in rat liver about two weeks after birth. We identified two clusters of DNaseI hypersensitive (HS) sites in the TO gene upstream region; one near the promoter, the other at a distant upstream location (-8.5 kb). Hypersensitivity of upstream sites was present in adult and in 7 day old rat liver, but absent in kidney. To investigate their role in transcriptional regulation, a reporter gene controlled by both HS site regions was used to generate transgenic mice. In these animals the transgene followed the cell specific and developmental regulation of the endogenous gene: inactive after birth and active in adult liver. Transgenes containing only the promoter proximal HS site were non-functional. [less ▲]

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See detailDNase I-sensitive sites within the nuclear architecture visualized by immunoelectron microscopy.
Thiry, Marc ULg

in DNA & Cell Biology (1991), 10(3), 169-80

Nick-translation using mild digestion with DNase I allows preferential labeling of actively transcribing or potentially active genes, as compared with inactive genes. We have adapted this method to the ... [more ▼]

Nick-translation using mild digestion with DNase I allows preferential labeling of actively transcribing or potentially active genes, as compared with inactive genes. We have adapted this method to the level of electron microscopy to see the DNase I-sensitive regions in situ in Ehrlich tumor cells. In interphase cells treated with very low concentrations of DNase I, labeled sequences are found at the borders and in the close vicinity of condensed chromatin blocks. Labeling of condensed areas of chromatin requires higher DNase I concentrations and longer incubation in the nick-translation medium. In the nucleolus, the first sites to be nick-translated are the fibrillar centers and the interstices surrounding them, whereas the dense fibrillar component never contains labeled sequences. When cells are pretreated with actinomycin D, only a few perinucleolar clumps of condensed chromatin are labeled under the same conditions. This method provides a new tool for studying the functional organization of chromatin within a cell. The precise location of nick-translated sites in nucleolar components observed could change classical views concerning the functional organization of the nucleolus. [less ▲]

Detailed reference viewed: 8 (0 ULg)