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)

Thymidine kinase (TK)-negative (TK-) mutant strains of herpes simplex virus type 1 (HSV-1) show reduced expression of alpha and beta viral genes during acute infection of trigeminal ganglion neurons following corneal infection (M. Kosz-Vnenchak, D. M. Coen, and D. M. Knipe, J. Virol. 64:5396-5402, 1990). It was surprising that a defect in a beta gene product would lead to decreased alpha and beta gene expression, given the regulatory pathways demonstrated for HSV infection of cultured cells. In this study, we have examined viral gene expression during reactivation from latent infection in explanted trigeminal ganglion tissue. In explant reactivation studies with wild-type virus, we observed viral productive gene expression over the first 48 h of explant incubation occurring in a temporal order (alpha, beta, gamma) similar to that in cultured cells. This occurred predominantly in latency-associated transcript-positive neurons but was limited to a fraction of these cells. In contrast, TK- mutant viruses showed greatly reduced alpha and beta gene expression upon explant of latently infected trigeminal ganglion tissue. An inhibitor of viral TK or an inhibitor of viral DNA polymerase greatly decreased viral lytic gene expression in trigeminal ganglion tissue latently infected with wild-type virus and explanted in culture. These results indicate that the regulatory mechanisms governing HSV gene expression are different in trigeminal ganglion neurons and cultured cells. We present a new model for viral gene expression in trigeminal ganglion neurons with implications for the nature of the decision process between latent infection and productive infection by HSV.
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PMID:Evidence for a novel regulatory pathway for herpes simplex virus gene expression in trigeminal ganglion neurons. 839 54

For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).
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PMID:Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML. 864 57

A novel L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), was found to be a potent and selective inhibitor of Epstein-Barr virus (EBV) replication. The decrease in the amount of viral production was concentration dependent with a 90% inhibitory concentration of approximately 5 muM. Upon removal of the drug from treated cells, virus production resumed in 21 days. Metabolism studies indicated that L-FMAU could be converted to its mono-,di- and triphosphate metabolites in both EBV producing and non-producing cells than in EBV non-producing cells. The mechanism of selectivity of L-FMAU against EBV producing cells. However, the amount of L-FMAU nucleotides formed was three times larger in EBV producing cells than in EBV non-producing cells. The mechanism of selectivity of L-FMAU against EBV does not appear to be due solely to the preferential phosphorylation of L-FMAU in EBV producing cells. The triphosphate of L-FMAU could not be utilized as a substrate by EBV DNA polymerase or the human DNA polymerases alpha, beta, gamma, or delta. Therefore, the incorporation of L-FMAU residues into viral DNA may not be the mechanism of antiviral activity. This compound appears to have a mechanism of action different from that of any other antiherpes virus nucleoside analogs. In addition, L-FMAU has very low cytotoxicity with 50% inhibition of cell growth occurring at a concentration of 1mM. Given the potent inhibitory activity of this compound against EBV and its inability to be incorporated into cellular DNA, L-FMAU analogs should be explored as a new class of anti-EBV agents.
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PMID:Inhibition of Epstein-Barr virus replication by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil. 865 44

There are five well-characterized nuclear DNA polymerases in eukaryotes (DNA polymerases alpha, beta, delta, epsilon and zeta) and this short review summarizes our current knowledge concerning the participation of each in DNA-repair. The three major DNA excision-repair pathways involve a DNA synthesis step that replaces altered bases or nucleotides removed during repair. Base excision-repair removes many modified bases and abasic sites, and in mammalian cells this mainly involves DNA polymerase beta. An alternative means for completion of base excision-repair, involving DNA polymerases delta or epsilon, may also operate and be even more important in yeast. Nucleotide excision-repair uses DNA polymerases delta or epsilon to resynthesize the bases removed during repair of pyrimidine dimers and other bulky adducts in DNA. Similarly, mismatch-repair of replication errors appears to involve DNA polymerases delta or epsilon. DNA polymerase alpha is required for semi-conservative replication of DNA but not for repair of DNA. A more recently discovered enzyme, DNA polymerase zeta, appears to be involved in the bypass of damage, without excision, and occurs during DNA replication of a damaged template.
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PMID:Which DNA polymerases are used for DNA-repair in eukaryotes? 911 Nov 89

The changes in the distribution of DNA polymerase alpha in nuclei from HL-60 cells treated with Methotrexate (MTX) for up to 15 hr. were checked by means of both confocal analysis and electron microscopy analysis. The results provided evidence that, relative to controls, in the MTX treated cells the enzyme undergoes a topographical rearrangement throughout the nucleus, showing a pattern of distribution which calls to mind the nuclear matrix structure. The "in vitro" analysis of DNA polymerases alpha, beta, and gamma activities revealed that, in nuclei from control cells, DNA polymerase alpha was the principal DNA polymerase driving this "in vitro" system, while after 15 hr. of MTX treatment its activity was largely decreased and replaced by DNA polymerase beta, which is believed to be associated with DNA repair. Taken together, these results suggest that among the intracellular processes elicited by MTX-induced apoptosis in HL60 cells, the redistribution of DNA polymerase alpha and the stimulation of DNA polymerase beta activity might represent an extreme attempt of the cell to preserve the replicative machinery during fragmentation and chromatin margination.
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PMID:Shift of DNA polymerase alpha nuclear distribution and activity in apoptotic human leukaemia cells. 917 64

The treatment of tamoxifen, widely used as adjuvant chemotherapy for breast cancer, increases significantly the risk of developing endometrial cancer. The miscoding properties of tamoxifen-derived DNA adducts, alpha-(N2-deoxyguanosinyl)tamoxifens (dG-N2-tamoxifen), have been explored, using an in vitro experimental system to quantify base substitutions and deletions. Site-specifically modified oligodeoxynucleotides containing an epimer of trans- and cis-forms of dG-N2-tamoxifens were prepared postsynthetically and used as templates in primer extension reactions catalyzed by mammalian DNA polymerases alpha, beta, and delta. Pol alpha catalyzed incorporation of dCMP and dAMP opposite all four stereoisomers of dG-N2-tamoxifen, accompanied by lesser amounts of dGMP. In contrast, pol delta catalyzed preferential incorporation of dCMP, a correct base, opposite the lesions; one of the trans-forms of dG-N2-tamoxifens only promoted incorporation of dTMP. Using pol beta, preferential incorporation of dCMP, along with small amounts of incorporation of dAMP and dGMP, was detected. One- and two base deletions were also observed with pol alpha and pol beta. The miscoding specificities and frequencies of dG-N2-tamoxifens varied depending on the DNA polymerase used. In addition, with pol alpha and pol beta, large amounts of 5-base deletions were preferentially formed at the cis-forms of dG-N2-tamoxifen, but not at the trans-forms of dG-N2-tamoxifen. We conclude that dG-N2-tamoxifen adducts have high miscoding potentials.
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PMID:Miscoding potential of tamoxifen-derived DNA adducts: alpha-(N2-deoxyguanosinyl)tamoxifen. 933 62

A sulfated glycoglycerolipid, 1-O-(6'-sulfo-alpha-D-glucopyranosyl)-2,3-di-O-phytanyl- sn-glycerol (KN-208), a derivative of the polar lipid isolated from an archaebacterium, strongly inhibited DNA polymerase (pol) alpha and pol beta in vitro among 5 eukaryotic DNA polymerases (alpha, beta, gamma, delta, and epsilon). It also inhibited Escherichia coli DNA polymerase I Klenow fragment (E. coli pol I) and human immunodeficiency virus reverse transcriptase (HIV RT). The mode of inhibition of these polymerases was competitive with the DNA template primer and was non-competitive with the substrate dTTP. KN-208 inhibited pol beta most strongly, with a Ki value of 0.05 microM, 10-fold lower than that for pol alpha (0.5 microM) and 60- or 140-fold lower than that for HIV RT (3 microM) or for E. coli pol I (7 microM), respectively. The loss of sulfate on the 6'-position of glucopyranoside of this compound completely abrogated inhibition. However, the hydrophilic part of KN-208, glucose 6-sulfate alone, showed no inhibition. Other sulfated compounds containing different hydrophobic structures, such as dodecyl sulfate and cholesterol sulfate, exhibited a much weaker inhibition. Our results suggest that the whole molecular structure of KN-208 is required for inhibition. KN-208 was shown to be modestly cytotoxic for the human leukemic cell line K562. Interestingly, a subcytotoxic dose of KN-208 increased the sensitivity of the human leukemic cells to an alkylating agent, methyl methanesulfonate, while it did not potentiate the effects of ultraviolet light or of cisplatin.
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PMID:Sulfated glycoglycerolipid from archaebacterium inhibits eukaryotic DNA polymerase alpha, beta and retroviral reverse transcriptase and affects methyl methanesulfonate cytotoxicity. 959 Jan 27

DNA polymerases catalyze the synthesis of DNA using a continuous uninterrupted template strand. However, it has been shown that a 3'-->5' exonuclease-deficient form of the Klenow fragment of Escherichia coli DNA polymerase I as well as DNA polymerase of Thermus aquaticus can synthesize DNA across two unlinked DNA templates. In this study, we used an oligonucleotide-based assay to show that discontinuous DNA synthesis was present in HeLa cell extracts. DNA synthesis inhibitor studies as well as fractionation of the extracts revealed that most of the discontinuous DNA synthesis was attributable to DNA polymerase alpha. Additionally, discontinuous DNA synthesis could be eliminated by incubation with an antibody that specifically neutralized DNA polymerase alpha activity. To test the relative efficiency of each nuclear DNA polymerase for discontinuous synthesis, equal amounts (as measured by DNA polymerase activity) of DNA polymerases alpha, beta, delta (+/- PCNA) and straightepsilon (+/- PCNA) were used in the discontinuous DNA synthesis assay. DNA polymerase alpha showed the most discontinuous DNA synthesis activity, although small but detectable levels were seen for DNA polymerases delta (+PCNA) and straightepsilon (- PCNA). Klenow fragment and DNA polymerase beta showed no discontinuous DNA synthesis, although at much higher amounts of each enzyme, discontinuous synthesis was seen for both. Discontinuous DNA synthesis by DNA polymerase alpha was seen with substrates containing 3 and 4 bp single-strand stretches of complementarity; however, little synthesis was seen with blunt substrates or with 1 bp stretches. The products formed from these experiments are structurally similar to that seen in vivo for non-homologous end joining in eukaryotic cells. These data suggest that DNA polymerase alpha may be able to rejoin double-strand breaks in vivo during replication.
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PMID:DNA synthesis on discontinuous templates by human DNA polymerases: implications for non-homologous DNA recombination. 968 89

Lithocholic acid (LCA), one of the major components in secondary bile acids, promotes carcinogenesis in rat colon epithelial cells induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which methylates DNA. Base-excision repair of DNA lesions caused by the DNA methylating agents requires DNA polymerase beta (pol beta). In the present study, we examined 17 kinds of bile acids with respect to inhibition of mammalian DNA polymerases in vitro. Among them, only LCA and its derivatives inhibited DNA polymerases, while other bile acids were not inhibitory. Among eukaryotic DNA polymerases alpha, beta, delta, epsilon, and gamma, pol beta was the most sensitive to inhibition by LCA. The inhibition mode of pol beta was non-competitive with respect to the DNA template-primer and was competitive with the substrate, dTTP, with the Ki value of 10 microM. Chemical structures at the C-7 and C-12 positions in the sterol skeleton are important for the inhibitory activity of LCA. This inhibition could contribute to the tumor-promoting activity of LCA.
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PMID:Lithocholic acid, a putative tumor promoter, inhibits mammalian DNA polymerase beta. 991 84

Pyrimidine (6-4) pyrimidone photodimers are major photoproducts that have mutagenic and carcinogenic consequences. One major reason for these biological effects of (6-4) photoproducts may be base mispairing/DNA replication errors due to hydrogen bonding to bases opposite these damaged sites. We synthesized a modified 41-mer DNA containing a (6-4) photoproduct using a preformed building block, then employed it as a template for primer extension reactions catalyzed by Klenow fragment and DNA polymerases alpha, beta and delta (pol alpha, pol beta and pol delta). None of these DNA polymerases were able to bypass the (6-4) photoproduct and elongation terminated at or near the 3'-pyrimidone of the photoproduct, depending on the dNTP concentration. When a single-chain Fv (scFv) with high affinity for the (6-4) photoproduct was included in the polymerization reaction, DNA synthesis was inhibited at base positions four, six, eight or eight nucleotides prior to the 3'-pyrimidone by Klenow fragment, pol alpha, pol beta or pol delta, respectively. These results suggest that the scFv can bind to the template DNA containing a (6-4) photoproduct and inhibit extension reactions by polymerases.
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PMID:Effects of a high-affinity antibody fragment on DNA polymerase reactions near a (6-4) photoproduct site. 1004 14


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