Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain perivascular macrophages are a major target of simian immunodeficiency virus (SIV) infection in rhesus macaques and HIV infection in humans. Perivascular macrophages are distinct from parenchymal microglia in their location, morphology, expression of myeloid markers, and turnover in the CNS. In contrast to parenchymal microglia, perivascular macrophages are continuously repopulated by blood monocytes, which undergo maturation to macrophages on entering the central nervous system (CNS). We studied differences in monocyte/macrophages in vivo that might account for preferential infection of perivascular macrophages by SIV. In situ hybridization for SIV and proliferating cellular nuclear antigen (PCNA) immunohistochemistry demonstrated that SIV-infected and PCNA-positive cells were predominantly found in perivascular cuffs of viremic animals and in histopathological lesions that characterize SIV encephalitis (SIVE) in animals with AIDS. Multilabel techniques including double-label immunohistochemistry and combined in situ hybridization and immunofluorescence confocal microscopy revealed numerous infected perivascular macrophages that were PCNA-positive. Outside the CNS, SIV-infected, PCNA-expressing macrophage subpopulations were found in the small intestine and lung of animals with AIDS. While PCNA is used as a marker of cell proliferation it is also strongly expressed in non-dividing cells undergoing DNA synthesis and repair. Therefore, more specific markers for cell proliferation including Ki-67, topoisomerase IIalpha, and bromodeoxyuridine (BrdU) incorporation were used which indicated that PCNA-positive cells within SIVE lesions were not proliferating. These observations are consistent with perivascular macrophages as terminally differentiated, non-dividing cells and underscores biological differences that could potentially define mechanisms of preferential, productive infection of perivascular macrophages in the rhesus macaque model of neuroAIDS. These studies suggest that within CNS and non-CNS tissues there exist subpopulations of macrophages that are SIV-infected and express PCNA.
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PMID:Proliferating cellular nuclear antigen expression as a marker of perivascular macrophages in simian immunodeficiency virus encephalitis. 1216 82

Bloom syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one of the complexes, termed BRAFT, also contains five of the Fanconi anemia (FA) complementation group proteins (FA proteins). FA resembles BS in genomic instability and cancer predisposition, but most of its gene products have no known biochemical activity, and the molecular pathogenesis of the disease is poorly understood. BRAFT displays a DNA-unwinding activity, which requires the presence of BLM because complexes isolated from BLM-deficient cells lack such an activity. The complex also contains topoisomerase IIIalpha and replication protein A, proteins that are known to interact with BLM and could facilitate unwinding of DNA. We show that BLM complexes isolated from an FA cell line have a lower molecular mass. Our study provides the first biochemical characterization of a multiprotein FA complex and suggests a connection between the BLM and FA pathways of genomic maintenance. The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair.
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PMID:A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. 1272 1

The chromatin environment and the sites of integration in the host genome are critical determinants of human immunodeficiency virus (HIV) transcription and replication. Depending on the chromosomal location of provirus integration within the genome, HIV-1 long terminal repeat (LTR)-mediated transcription may vary from 0- to 70-fold. Cis-elements such as topoisomerase II cleavage sites, Alu repeats and matrix attachment regions (MARs) are thought to be targets for retroviral integration. Here we show that a novel MAR sequence from the T-cell receptor beta locus (MARbeta) and the IgH MAR mediate transcriptional augmentation when placed upstream of the HIV-1 LTR promoter. The effect of transcriptional augmentation is seen in both transient and stable transfection, indicating its effect even upon integration in the genome. MAR-mediated transcriptional elevation is independent of Tat, and occurs synergistically in the presence of Tat. Further, we show that MAR-mediated transcriptional elevation is specific to the HIV-1 LTR and the Moloney murine leukemia virus LTR promoter. In a transient transfection assay using over-expressed IkappaB, the inhibitor of NF-kappaB, we show that MAR-induced processive transcription is NF-kappaB dependent, signifying the role of local enhancers within the LTR promoter. Furthermore, by RNase protection experiments using proximal and distal probes, we show that MAR-mediated transcriptional upregulation is more prominent at the distal rather than the proximal end, thus indicating the potential role of MARs in promoting elongation.
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PMID:Stimulation of Tat-independent transcriptional processivity from the HIV-1 LTR promoter by matrix attachment regions. 1279 52

Some anticancer drugs, but not all, inhibit replication of human immunodeficiency virus (HIV) and thus, exhibit a therapeutic potential. Such drugs, unlike the traditional HIV enzyme inhibitors, could suppress HIV strains that are resistant to inhibitors of viral enzymes, decrease proviral burden in vivo, or reduce reservoirs of infection via killing infected cells. Thus, they may be an effective adjunct therapy or perhaps result in a cure. The incidence of HIV infection and AIDS mortalities continue to increase worldwide, including the United States and parts of Africa, with a parallel increase in a number of other manifestations, including AIDS defining malignancies. The basis for continual spread of HIV presumably in large part stems from the viral resistance to previously successful drugs and the lack of curative antiretroviral drugs. To reverse these trends, other approaches for AIDS therapy must be developed. One possibility is the development of potent anticancer drugs, that exhibit anti-HIV activities. At least four chemically and pharmacologically distinct classes of anticancer drugs, i.e. certain cyclin-dependent kinase inhibitors (CDKIs), topoisomerase 1 enzyme (top 1) inhibitors, non-nucleoside antimetabolites, and estrogen receptor ligands are promising candidates. These drugs, at high doses are used for cancer therapy; at lower concentrations they exhibit anti-HIV activities in cultured cells. While the antiretroviral and the anticancer activities of the cdk inhibitor flavopiridol appear to be mutually exclusive and unrelated in cells and animal model(s) of HIV disease, the top 1 inhibitor 9-nitrocamptothecin, as well as the cdk-inhibitor roscovitine inhibit replication of HIV via selective sensitization of HIV-infected cells to apoptosis. In contrast, the inhibitory effects of these compounds are different from other cancer therapeutics that, at toxic concentrations, activate HIV either in cultured cells (such as certain ingenol and butyrate derivatives) and/or in patients (such as the widely used cyclophosmamide and cisplatin). This quality may lead to the eradication of proviral reservoirs, which is not accomplished by the currently available antiretroviral drugs. In this review, relevant available clinical and in vitro data that either support or discourage using certain anticancer drugs for treatment of HIV disease, and the rationales for developing novel antiretroviral drugs that may target infected cells rather than viral proteins are discussed.
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PMID:A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics. 1467 May 89

Replication of Streptomyces linear chromosomes and plasmids proceeds bidirectionally from a central origin, leaving recessed 5' termini that are extended by a telomere binding complex. This complex contains both a telomere-protecting terminal protein (Tpg) and a telomere-associated protein that interacts with Tpg and the DNA ends of linear Streptomyces replicons. By using histidine-tagged telomere-associated protein (Tap) as a scaffold, we identified DNA polymerase (PolA) and topoisomerase I (TopA) proteins as other components of the Streptomyces telomere complex. Biochemical characterization of these proteins indicated that both PolA and TopA exhibit highly efficient reverse transcriptase (RT) activity in addition to their predicted functions. Although RT activity innate to other DNA-dependent DNA polymerases has been observed previously, its occurrence in a topoisomerase is unprecedented. Deletion mapping and sequence analysis showed that the RT activity of Streptomcyces TopA resides in a peptide region containing motifs that are absent from most bacterial topoisomerases but are highly conserved in a novel subfamily of eubacterial topoisomerases found largely in Actinobacteria. Within one of these motifs, and essential to the RT function of Streptomyces TopA, is an Asp-Asp doublet sequence required also for the RT activities of human immunodeficiency virus and eukaryotic cell telomerases.
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PMID:Reverse transcriptase activity innate to DNA polymerase I and DNA topoisomerase I proteins of Streptomyces telomere complex. 1545 10

We have identified four small molecules that boost transduction of cells by human immunodeficiency virus (HIV) and investigated their mechanism of action. These molecules include etoposide and camptothecin, which induce DNA damage by inhibiting religation of cleaved topoisomerase-DNA complexes, taxol, which interferes with the function of microtubules, and aphidicolin, which inhibits DNA polymerases. All four compounds arrest the cell cycle at G2/M, though in addition high concentrations of aphidicolin arrest in G1. We find that early events of HIV replication, including synthesis of late reverse transcription products, two-long terminal repeat circles, and integrated proviruses, were increased after treatment of cells with concentrations of each compound that arrested in G2/M. Stimulation was seen for both transformed cell lines (293T and HeLa cells) and primary cells (IMR90 lung fibroblasts). Arrest in G1 with high concentrations of aphidicolin boosted transduction, though not much as with lower concentrations that arrested in G2/M. Arrest of IMR90 cells in G1 by serum starvation and contact inhibition reduced transduction. Previously, the proteasome inhibitor MG132 was reported to increase HIV infection-here we investigated the effects of combinations of the cell cycle inhibitors with MG132 and obtained data suggesting that MG132 may also boost transduction by causing G2/M cell cycle arrest. These data document that cell cycle arrest in G2/M boosts the early steps of HIV infection and suggests methods for increasing transduction with HIV-based vectors.
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PMID:Cell cycle arrest in G2/M promotes early steps of infection by human immunodeficiency virus. 1582 84

Human immunodeficiency virus (HIV) reverse transcription can be notably affected by cellular activation, differentiation, and division. We hypothesized that changes in the cell cycle could also affect HIV susceptibility to nucleoside analogues, which compete with natural nucleotides for incorporation into viral DNA and inhibit viral replication through premature termination of reverse transcription. Proliferating HeLa-derived indicator cells were arrested in the S/G2 phase with etoposide, a topoisomerase II inhibitor, or in the G1/S phase with aphidicolin, a polymerase alpha inhibitor. Cell cycle arrest by both agents induced a remarkable decrease in HIV susceptibility to zidovudine (AZT). This decrease was seen both with a single-cycle infectivity assay and with a viral DNA quantitation assay, indicating that the effect of cell cycle arrest was exerted at the reverse transcription stage. The increase in the 50% inhibitory concentration (IC50) seen with arrested cells was strongest for AZT (23-fold) and stavudine (21-fold) but more modest for other drugs (lamivudine, 11-fold; dideoxyinosine, 7-fold; and nevirapine, 3-fold). In drug-resistant reverse transcriptase mutants, the increase in AZT IC50 (relative to that in dividing cells) was most prominent with a Q151M mutant and was comparable to the wild type in other drug-resistant mutants. Quantitation of intracellular pools of dTTP and AZT 5'-triphosphate (AZTTP) showed that etoposide treatment induced a significant increase in intracellular dTTP and consequently a decrease in AZTTP/dTTP ratios, suggesting that the decrease in viral susceptibility to AZT was caused by reduced incorporation of the analogue into nascent viral DNA. These results emphasize the importance of cellular proliferation and deoxynucleoside triphosphate metabolism in HIV susceptibility to nucleoside analogues and underscore the need to study the activities of drugs of this class with natural target cells under physiological conditions of activation and proliferation.
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PMID:Effect of cell cycle arrest on the activity of nucleoside analogues against human immunodeficiency virus type 1. 1628 81

Promyelomonocytic leukemia (PML) is a prominent oncosuppressor whose inactivation is involved in the pathogenesis of hematological and epithelial cancers. Here, we report that PML aggregated in nuclear bodies in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. PML aggregation occurred after the fusion of nuclei (karyogamy) within syncytia but before the apoptotic program was activated. The aggregation of PML was detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Using a range of specific inhibitors of PML (the oncogenic PML/RARalpha fusion product or specific small interfering RNAs), we demonstrated that, in Env-elicited syncytia, PML was required for activating phosphorylation of ataxia telangiectasia mutated (ATM), which colocalized with PML in nuclear bodies, in a molecular complex that also involved topoisomerase IIbeta-binding protein 1. PML knockdown thus inhibited the ATM-dependent DNA damage response that culminates in the activation of p53, p53-dependent transcription of pro-apoptotic genes and cell death. Infection of CD4-expressing cells with HIV-1 also induced syncytial apoptosis, which could be suppressed by inhibiting PML. Altogether, these data indicate that PML activation is a critical early event that participates in the apoptotic demise of HIV-1-elicited syncytia.
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PMID:The tumor suppressor protein PML controls apoptosis induced by the HIV-1 envelope. 1902 33

All organisms possess at least one type IA DNA topoisomerase. These topoisomerases function as part of a DNA structure-specific "dissolvasome," also known as the RTR complex, which has critical functions in faithful DNA replication, recombination, and chromosome segregation. In humans, the heteromeric RTR complex consists of RMI1, RMI2, the Bloom's syndrome gene product (BLM), and topoisomerase 3A (TOP3A) proteins. Here, we describe the identification and characterization of two deleterious mutations in the zebrafish top3a gene that reveal an unexpected tissue-specific requirement of top3a function in developing thymocytes. Deficiency in top3a activates a p53-dependent check-point but does not affect VDJ recombination. Our results suggest that TOP3A could be a candidate gene involved in human primary immunodeficiency syndromes.
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PMID:Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha. 2062 52

We report the emergence of a multidrug-resistant Haemophilus influenzae strain in a patient with common variable immunodeficiency suffering from recurrent bronchopneumonia caused by H. influenzae. After the patient had received several antibiotic therapies, a strain was isolated showing resistance to ampicillin, ampicillin/sulbactam, cefazolin, cefuroxime, ciprofloxacin, and clarithromycin. Polymerase chain reaction analyses and sequencing revealed the presence of the beta-lactamase gene bla(TEM-1), two mutations (A502T and R517H) in the ftsI gene encoding the transpeptidase region of the penicillin-binding protein 3, and one mutation in the ribosomal protein gene L4 (G65D) conferring resistance to beta-lactams and macrolides, respectively. Additionally, the plasmid-encoded aac(6')-Ib-cr gene mediating slightly reduced susceptibility to quinolones and two mutations in the DNA gyrase gene gyrA and one mutation in the topoisomerase IV gene parC were identified leading to a high-level fluoroquinolone-resistant phenotype. In conclusion, the treatment of H. influenzae infections accompanied by high bacterial loads such as bronchopneumonia can be complicated by the selection of multidrug-resistant strains. Moreover, the emergence of aac(6')-Ib-cr in H. influenzae causing low fluoroquinolone resistance levels might have contributed to the selection of DNA gyrase and topoisomerase IV mutants.
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PMID:Emergence of a multidrug-resistant Haemophilus influenzae strain causing chronic pneumonia in a patient with common variable immunodeficiency. 2309 85


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