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:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously identified retroperitoneal fibromatosis-associated herpesvirus (RFHV) as a simian homolog of Kaposi's sarcoma-associated herpesvirus (KSHV) in a fibroproliferative malignancy of macaques that has similarities to Kaposi's sarcoma. In this report, we cloned 4.3 kb of divergent locus B (DL-B) flanking the DNA polymerase gene from two variants of RFHV from different species of macaque with a consensus degenerate hybrid oligonucleotide primer approach. Within the DL-B region of RFHV, viral homologs of the cellular interleukin-6, dihydrofolate reductase, and thymidylate synthase genes were identified, along with a homolog of the gammaherpesvirus open reading frame (ORF) 10. In addition, a homolog of the KSHV ORF K3, the modulator of immune recognition-1, was identified. Our data show a close similarity in sequence conservation, gene content, and genomic structure between RFHV and KSHV which strongly supports the grouping of these viral species within the same RV-1 rhadinovirus lineage and the hypothesis that RFHV is the macaque homolog of KSHV.
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PMID:Analysis of 4.3 kilobases of divergent locus B of macaque retroperitoneal fibromatosis-associated herpesvirus reveals a close similarity in gene sequence and genome organization to Kaposi's sarcoma-associated herpesvirus. 1269 11

The novel antitumor compound NC-190 strongly inhibited the growth of FM3A cells with an IC50 of 0.019 microg/ml (0.042 microM) when cultured with NC-190 for 48 h. NC-190 potently suppressed DNA synthesis, with 90% inhibition observed at 0.1 microg/ml of NC-190. RNA and protein syntheses were also suppressed under the same conditions, but to a lesser extent. We then measured the cellular enzymatic activities of DNA polymerase alpha, RNA polymerase, thymidine kinase, thymidylate synthase and Leu-tRNA synthetase of FM3A cells cultured with or without NC-190. Of these 5 enzymes, the activity of thymidine kinase was most strongly suppressed by NC-190, by 77%. Although NC-190 did not directly inhibit the activitiy of thymidine kinase in a cell-free system, expression of mRNA of thymidine kinase was suppressed by 75% in NC-190-treated cells. These results indicate that NC-190 can suppress the expression of the gene for thymidine kinase and the inhibition of thymidine kinase contributes to the inhibition of cell growth by NC-190 together with the inhibition of topoisomerase II.
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PMID:The topoisomerase II-inhibitor NC-190 reduces the level of thymidine kinase mRNA in murine tumor cells. 1463 16

No backbone motif other than phospho-ribose and phospho-deoxyribose has been found in natural nucleic acids, currently restricting the molecular types of replicable biopolymers to DNA and RNA. With the aim of propagating and expressing a third type of nucleic acid in vivo, we assessed the replicability of polynucleotides with a phospho-hexitol backbone (HNA) in vivo and in vitro. Faithful polymerisation of up to four deoxynucleotides templated by hexitol oligonucleotides was established in vitro using DNA polymerase from Escherichia coli (PolA Klenow exo-fragment) and Thermus aquaticus (Taq polymerase). Condensation of up to three successive hTTPs (hexitol thymidine triphosphate) in responses to a pentameric hexitol template (hA)5 could also be demonstrated in vitro. Such a marginal HNA-dependent HNA polymerase activity of natural polymerases may be evolved in the future to catalyse in vitro amplification of HNA. The transmission of a two-codon-long genetic message carried on a hexameric hexitol template was also established using a selection screen for restoring thymidylate synthase activity in E. coli. These results exemplify the potential that can be explored by converting artificial substrates with natural enzymes in the field of informational polymer synthesis.
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PMID:Replication of hexitol oligonucleotides as a prelude to the propagation of a third type of nucleic acid in vivo. 1474 72

An adequate supply of nucleotides is essential for DNA replication and DNA repair. Moreover, inhibition of TTP synthesis can cause cell death by a poorly characterized mechanism called thymine-less death. In the yeast Saccharomyces cerevisiae, the genes encoding thymidylate synthetase (CDC21) and thymidylate kinase (CDC8) are both essential for de novo TTP synthesis. The effects of temperature-sensitive mutations in these genes have been characterized and, curiously, the phenotypes displayed by cells harboring them include shortened telomeric repeat tracts. This finding raised the possibility that the enzyme telomerase is very sensitive to TTP-pools. We tested this possibility in vivo by assessing telomerase-dependent extension in situations of lowered TTP supply. The results show that the above-mentioned short telomere phenotype is not a consequence of an inability of telomerase to elongate telomeres when TTP synthesis is impaired. Moreover, this telomere shortening was abolished in cells harboring a mutation in DNA polymerase alpha. Previously, this same mutation was shown to affect the coordination between conventional replication and telomerase-mediated extension. These results thus re-emphasize the importance of the interplay between conventional replication and telomerase-mediated addition of telomeric repeats in telomere replication.
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PMID:Limited TTP supply affects telomere length regulation in a telomerase-independent fashion. 1568 20

Bacteriophage PhiJL001 infects a novel marine bacterium in the alpha subclass of the Proteobacteria isolated from the marine sponge Ircinia strobilina. PhiJL001 is a siphovirus and forms turbid plaques on its host. The genome sequence of PhiJL001 was determined in order to better understand the interaction between the marine phage and its sponge-associated host bacterium. The complete genome sequence of PhiJL001 comprised 63,469 bp with an overall G+C content of 62%. The genome has 91 predicted open reading frames (ORFs), and 17 ORFs have been assigned putative functions. PhiJL001 appears to be a temperate phage, and the integrase gene was identified in the genome. DNA hybridization analysis showed that the PhiJL001 genome does not integrate into the host chromosome under the conditions tested. DNA hybridization experiments therefore suggested that PhiJL001 has some pseudolysogenic characteristics. The genome of PhiJL001 contains many putative genes involved in phage DNA replication (e.g., helicase, DNA polymerase, and thymidylate synthase genes) and also contains a putative integrase gene associated with the lysogenic cycle. Phylogeny based on DNA polymerase gene sequences indicates that PhiJL001 is related to a group of siphoviruses that infect mycobacteria. Designation of PhiJL001 as a siphovirus is consistent with the morphology of the phage visualized by transmission electron microscopy. The unique marine phage-host system described here provides a model system for studying the role of phages in sponge microbial communities.
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PMID:Genomic analysis of bacteriophage PhiJL001: insights into its interaction with a sponge-associated alpha-proteobacterium. 1574 65

As a general rule, enzymes act on only one enantiomer of a chiral substrate and only one of the enantiomeric forms of a chiral molecule may bind effectively at the catalytic site, displaying biological activity. In recent years, some exceptions have been found among viral and cellular enzymes involved in the synthesis of deoxynucleoside triphosphates and in their polymerisation into DNA. Examples are: herpes virus thymidine kinases, cellular deoxycytidine kinase and deoxynucleotide kinases, human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, hepatitis B virus (HBV) DNA polymerase and, to a lesser extent, some cellular DNA polymerases. The lack of enantioselectivity allows herpes simplex virus (HSV) thymidine kinase and cellular deoxycytidine kinase to phosphorylate the unnatural L-beta-enantiomers of D-thymidine and D-deoxycytidine, respectively, or of their analogues to monophosphate. This phosphorylation represents the first and often the rate-limiting step of their activation to triphosphates. The L-triphosphates can then exert antiviral (anti-HSV, anti-Human cytomegalovirus, anti-HIV-1, anti-HBV) and anticancer activities. Although only one L-nucleoside (3TC) has so far gained United States of America Food and Drug Administration (USA FDA) approval for clinical use against HIV-1, other L-enantiomers of nucleoside analogues, which have shown antiviral or anticancer activity in cell cultures are in clinical trials. Their resistance to enantioselective enzymes, such as thymidine phosphorylase, thymidylate synthase, (deoxy)-cytidine and dCMP deaminases, and their lower affinity for the mitochondrial thymidine kinase can ensure a higher selectivity and lower cytotoxicity with respect to those exerted by their corresponding natural D-enantiomers and might be exploited to solve problems arising during chemotherapy, such as metabolic inactivation, cytotoxicity and drug-resistance.
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PMID:Molecular basis for the antiviral and anticancer activities of unnatural L-beta-nucleosides. 1599 31

The localization of SeqA, thymidylate synthase, DnaB (helicase) and the DNA polymerase components alpha and tau, has been studied by immunofluorescence microscopy. The origin has been labelled through GFP-LacI bound near oriC. SeqA was located in the cell centre for one replication factory (RF) and at 1/4 and 3/4 positions in pre-divisional cells harbouring two RFs. The transition of central to 1/4 and 3/4 positions of SeqA appeared abrupt. Labelled thymidylate synthetase was found all over the cell, thus not supporting the notion of a dNTP-synthesizing complex exclusively localized near the RF. More DnaB, alpha and tau foci were found than expected. We have hypothesized that extra foci arise at pre-replication assembly sites, where the number of sites equals the number of origins, i.e. the number of future RFs. A reasonable agreement was found between predicted and found foci. In the case of multifork replication the number of foci appeared consistent with the assumption that three RFs are grouped into a higher-order structure. The RF is probably separate from the foci containing SeqA and the hemi-methylated SeqA binding sites because these foci did not coincide significantly with DnaB as marker of the RF. Co-labelling of DnaB and oriC revealed limited colocalization, indicating that DnaB did not yet become associated with oriC at a pre-replication assembly site. DnaB and tau co-labelled in the cell centre, though not at presumed pre-replication assembly sites. By contrast, alpha and tau co-labelled consistently suggesting that they are already associated before replication starts.
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PMID:Pre-replication assembly of E. coli replisome components. 1699 30

We determined the sequence of the 152,372 bp genome of phiYS40, a lytic tailed bacteriophage of Thermus thermophilus. The genome contains 170 putative open reading frames and three tRNA genes. Functions for 25% of phiYS40 gene products were predicted on the basis of similarity to proteins of known function from diverse phages and bacteria. phiYS40 encodes a cluster of proteins involved in nucleotide salvage, such as flavin-dependent thymidylate synthase, thymidylate kinase, ribonucleotide reductase, and deoxycytidylate deaminase, and in DNA replication, such as DNA primase, helicase, type A DNA polymerase, and predicted terminal protein involved in initiation of DNA synthesis. The structural genes of phiYS40, most of which have no similarity to sequences in public databases, were identified by mass spectrometric analysis of purified virions. Various phiYS40 proteins have different phylogenetic neighbors, including myovirus, podovirus, and siphovirus gene products, bacterial genes and, in one case, a dUTPase from a eukaryotic virus. phiYS40 has apparently arisen through multiple acts of recombination between different phage genomes as well as through acquisition of bacterial genes.
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PMID:Thermus thermophilus bacteriophage phiYS40 genome and proteomic characterization of virions. 1702 29

Oryctes rhinoceros virus (OrV) is an unassigned invertebrate dsDNA virus with enveloped and rod-shaped virions. Two cloned PstI fragments, C and D, of OrV DNA have been sequenced, consisting of 19,805 and 17,146 bp, respectively, and comprising about 30% of the OrV genome. For each of the two fragments, 20 open reading frames (ORFs) of 150 nucleotides or greater with no or minimal overlap were predicted. Ten of the predicted 40 ORFs revealed significant similarities to Heliothis zea virus 1 (HzV-1) ORFs, of which five, lef-4, lef-5, pif-2, dnapol and ac81, are homologues of conserved core genes in the family Baculoviridae, and one is homologous to baculovirus rr1. A baculovirus odv-e66 homologue is also present in OrV. Five ORFs encode proteins homologous to cellular thymidylate synthase (TS), patatin-like phospholipase, mitochondrial carrier protein, Ser/Thr protein phosphatase, and serine protease, respectively. TS is phylogenetically related to those of eukarya and nucleo-cytoplasmic large dsDNA viruses. However, the remaining 25 ORFs have poor or no sequence matches with the current databases. Both the gene content of the sequenced fragments and the phylogenetic analyses of the viral DNA polymerase suggest that OrV is most closely related to HzV-1. These findings and the re-evaluation of the relationship of HzV-1 to baculoviruses suggest that a new virus genus, Nudivirus, should be established, containing OrV and HzV-1, which are genetically related to members of the family Baculoviridae.
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PMID:Genomic analysis of Oryctes rhinoceros virus reveals genetic relatedness to Heliothis zea virus 1. 1710 21

Nickel(II) complexes of thiosemicarbazons were observed to be potent cytotoxic agents in human and rodent tissue cultured tumor cells. Each compound demonstrated a slightly different profile in the various histological types of tumors. The nickel complex of Appip demonstrated the most potent in vivo activity in the Ehrlich ascites carcinoma. This agent selectively inhibited L1210 DNA and purine syntheses, and DNA polymerase alpha, PRPP-amido transferase, IMP-dehydrogenase, dihydrofolate reductase, TMP-kinase and thymidylate synthetase activities. L1210 DNA strand scission was evident and DNA viscosity was reduced after 24 hr incubation. The nickel complexes were not L1210 DNA topoisomerase II inhibitors.
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PMID:Antineoplastic and Cytotoxic Activities of Nickel(II) Complexes of Thiosemicarbazones. 1847 74


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