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)

The capacity of human cells to modulate the synthesis of DNA repair enzymes has been investigated by measuring the induction of the uracil-DNA glycosylase during lymphocyte stimulation. Treatment of peripheral lymphocytes with phytohemagglutinin increased glycosylase activity 10-fold. Glycosylase stimulation was coordinate with the activation of DNA synthesis and DNA polymerase activity. Two chromatographically distinct species of the glycosylase have been resolved; only one species is induced during phytohemagglutinin stimulation. The effect of actinomycin D and cycloheximide on glycosylase induction was determined. Treatment with either inhibitor at 96 hr after phytohemagglutinin addition (maximal induction) decreased glycosylase activity after an appreciable lag period. This suggested that induction of the uracil-DNA glycosylase requires transcription and translation although the enzyme may be quite stable once induced.
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PMID:Induction of the DNA repair enzyme uracil-DNA glycosylase in stimulated human lymphocytes. 44 5

We have recently demonstrated that mammalian uracil-DNA glycosylase activity is undetectable in adult neurons. On the basis of this finding we hypothesized that uracil, derived either from oxidative deamination of cytosine or misincorporation of dUMP in place of dTMP during DNA repair by the unique nuclear DNA polymerase present in adult neurons, DNA polymerase beta, might accumulate in neuronal DNA. Uracil residues could also arise in the herpes simplex 1 (HSV1) genome during latency in nerve cells. We therefore suggest a role for the virus encoded uracil-DNA glycosylase in HSV1 reactivation and in the first steps of DNA replication. We show here 1) that the viral DNA polymerase incorporates dUTP in place of dTTP with a comparable efficiency in vitro; 2) that virus specific DNA/protein interactions between the virus encoded origin binding protein and its target DNA sequence is altered by the presence of uracil residues in its central region TCGCA. Thus uracil, present in viral OriS or other key sequences could hamper the process leading to viral reactivation. Hence, HSV1 uracil-DNA glycosylase, dispensable in viral proliferation in tissue culture, could be essential in neurons for the "cleansing" of the viral genome of uracil residues before the start of replication.
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PMID:Uracil in OriS of herpes simplex 1 alters its specific recognition by origin binding protein (OBP): does virus induced uracil-DNA glycosylase play a key role in viral reactivation and replication? 133 82

The activity of nuclear DNA polymerases alpha, beta and delta/epsilon, uracil-DNA glycosylase, thymidine kinase and the presence of Proliferating Cell Nuclear Antigen (PCNA) have been examined in developing rat glial cells, in rat and human glioma, in human neuroblastoma and in differentiated neuroblastoma cell lines in vitro. During glial development the activity of all enzymes tested, except DNA polymerase beta, markedly decreased, suggesting their coordinate regulation in respect to the proliferative state of the cells. Glioma and neuroblastoma cell lines restore the enzymatic activities that were no longer expressed in normal adult cells. Neuroblastoma cell lines induced to differentiate in vitro by retinoic acid showed a decline of the activities of DNA polymerase alpha, DNA polymerase delta/epsilon, uracil-DNA glycosylase and thymidine kinase similar to that observed during in vivo differentiation. We also demonstrate that PCNA is not detectable in glial and neuronal cells at all developmental stages, but can be found in tumor nerve cells. A possible use of enzymatic assays or anti-PCNA antibodies to detect brain tumors is discussed.
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PMID:DNA synthesis enzymes and proliferating cell nuclear antigen in normal and neoplastic nerve cells. 135 31

The extent and location of DNA repair synthesis in a double-stranded oligonucleotide containing a single dUMP residue have been determined. Gently prepared Escherichia coli and mammalian cell extracts were employed for excision repair in vitro. The size of the resynthesized patch was estimated by restriction enzyme analysis of the repaired oligonucleotide. Following enzymatic digestion and denaturing gel electrophoresis, the extent of incorporation of radioactively labeled nucleotides in the vicinity of the lesion was determined by autoradiography. Cell extracts of E. coli and of human cell lines were shown to carry out repair mainly by replacing a single nucleotide. No significant repair replication on the 5' side of the lesion was observed. The data indicate that, after cleavage of the dUMP residue by uracil-DNA glycosylase and incision of the resultant apurinic-apyrimidinic site by an apurinic-apyrimidinic endonuclease activity, the excision step is catalyzed usually by a DNA deoxyribophosphodiesterase rather than by an exonuclease. Gap-filling and ligation complete the repair reaction. Experiments with enzyme inhibitors in mammalian cell extracts suggest that the repair replication step is catalyzed by DNA polymerase beta.
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PMID:Generation of single-nucleotide repair patches following excision of uracil residues from DNA. 154 15

The antiviral distamycin A and its phenyl mustard derivative FCE24517 possessing antitumor activity were tested for their ability to inhibit macromolecular synthesis in three human and one murine cell line. While distamycin A was poorly active in these systems, FCE24517 inhibited DNA synthesis efficiently, RNA synthesis to a lower extent and had little effect on protein synthesis. These findings suggest that the in vivo activity of FCE24517 derives from the specific inhibition of DNA synthesis. When the two drugs were tested on several enzymes involved in human DNA metabolism a strikingly similar pattern of inhibition appeared, with distamycin A being the more potent. Both drugs showed: A), no inhibitory activity against thymidine kinase and DNA primase; B), low activity against DNA topoisomerases I and II and the 3'-5' exonuclease associated with the DNA polymerase epsilon; C), high activity against DNA polymerases alpha and epsilon, uracil-DNA glycosylase and the joining activity of the replicative DNA ligase; D), the highest inhibitory activity against the AMP-dependent DNA relaxing activity of DNA ligase. The strong in vitro inhibition of several DNA enzymatic activities, including DNA ligase, do not match with the in vivo activities of the two drugs. However a unique difference was observed: only FCE24517 inhibited the DNA-independent reaction of adenylation of human DNA ligase while the adenylation reaction of T4 and E. coli DNA ligase was unaffected by either drug. It is still unclear whether these properties are relevant for modulating the killing activity of FCE24517 against proliferating cells both in culture and in vivo. Nevertheless FCE24517 is the first known molecule capable of interacting directly and specifically with human DNA ligase.
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PMID:Specific inhibition of human DNA ligase adenylation by a distamycin derivative possessing antitumor activity. 170 93

The uracil-DNA glycosylase inhibitor gene (ugi) of the Bacillus subtilis bacteriophage PBS2 has been subcloned to a 720-base pair DNA fragment contained in pZW2-0.7 and its nucleotide sequence determined. Using nucleotide deletion analysis, we have located the cloned ugi gene along with potential regulatory elements. A promoter-like region (-10 and -35 consensus sequences) similar to other B. subtilis genes and the Shine-Dalgarno sequence characteristic of Gram-positive bacteria were both identified upstream from the initiator AUG codon. A 17-nucleotide exact inverted repeat followed by runs of adenine and thymine residues was positioned almost immediately downstream of the ochre codon. The ugi gene product was identified on sodium dodecyl sulfate-polyacrylamide gels using Escherichia coli minicells containing pZW2-0.7 and by recovering uracil-DNA glycosylase inhibitor activity following electrophoresis. The ugi gene codes for an acidic polypeptide of 9,477 molecular weight (84 amino acids) whose electrophoretic mobility was greater than predicted for a protein of this size. The mode of inhibition did not appear to involve a catalytic process nor did it directly involve inhibitor-DNA interaction. Rather, the inhibitor protein was shown to bind physically to the E. coli uracil-DNA glycosylase, forming a 36,000 molecular weight complex. This complex seems to be reversible, since inhibitor activity was recovered after heat treatment of the complex. In addition, we demonstrated that the inhibitor protein is active against uracil-DNA glycosylases isolated from several diverse biological sources but inactive against E. coli deoxyuridine triphosphatase, DNA polymerase I, and DNA polymerase alpha, beta, and gamma.
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PMID:Uracil-DNA glycosylase inhibitor gene of bacteriophage PBS2 encodes a binding protein specific for uracil-DNA glycosylase. 249 16

Infection of HSB-2 cells with human herpesvirus 6 (HHV6) results in an approximately 51-fold increase in the level of DNA polymerase activity and a 4.44-fold increase in the level of DNase activity when compared to mock-infected cells. There was no increase in thymidine kinase, uracil-DNA glycosylase, or deoxyuridine triphosphate nucleotidohydrolase activities in the infected cells. The HHV6-induced DNase and DNA polymerase activities could be distinguished from their normal cellular counterparts on the basis of immunological specificities and in the case of DNA polymerase based upon differences in electrophoretic migration. Serological studies also demonstrated reactivity of the antisera not only for HHV6 but also for Epstein-Barr virus.
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PMID:Demonstration of the human herpesvirus 6-induced DNA polymerase and DNase. 255 71

An insertion mutant of herpes simplex virus type 1 has been constructed which carries the lacZ gene from Escherichia coli within the coding sequence of gene UL2, which is in the long unique region of the genome. In a one-step growth curve experiment this recombinant (called in 1601) grew as well as the wild-type (wt) parent virus, indicating that the UL2 gene is dispensable for growth in tissue culture. Analysis of in 1601 DNA with restriction endonucleases showed no detectable changes from the wt apart from the insertion. Extracts of cells infected with in 1601 possessed levels of viral DNA polymerase and alkaline exonuclease activities similar to those infected with the wt, but unlike the wt had negligible uracil-DNA glycosylase activity, suggesting strongly that the product of the UL2 gene is the uracil-DNA glycosylase. The sequence of the uracil-DNA glycosylase gene of E. coli was recently published, and the encoded amino acid sequence of this shows clear similarity to that of UL2, confirming our results.
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PMID:Gene UL2 of herpes simplex virus type 1 encodes a uracil-DNA glycosylase. 256 40

A number of enzymes thought to be involved in DNA replication have been identified in the brain. These include single-stranded DNA-binding proteins, topoisomerases I and II, DNA polymerase alpha, a protein that binds Ap4A and might be classified as a DNA polymerase alpha accessory protein, RNase H, DNA polymerase beta, DNA ligase, an endo- and an exonuclease of unknown function, DNA methyl transferase and poly(ADPR) synthase. In contrast, little is known about the enzymology of DNA repair in brain. The few enzymes identified comprise uracil-DNA glycosylase, DNA polymerase beta, DNA polymerase alpha (which in neurons is present only at immature stages), DNA ligase, poly(ADPR) synthase, and O6-alkylguanine-DNA alkyltransferase. In addition, an exonuclease acting on depurinated single-stranded DNA (tentatively listed here as 3'----5' exonuclease), an endonuclease of unknown function as well as ill-defined acid and alkaline deoxyribonucleases also occur in brain.
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PMID:Enzymology of DNA replication and repair in the brain. 300 64

The effect of mercuric acetate on the activities of deoxyuridine triphosphate nucleotidohydrolase (dUTPase), DNA polymerase (alpha, beta), and uracil-DNA glycosylase has been studied in cultured human KB cells. There was a dose- and time-dependent inactivation of both dUTPase and DNA polymerase alpha activities by mercuric acetate. In cells exposed to low concentrations (10 microM) of mercuric acetate, dUTPase was most sensitive to inhibition with 30% of the activity being inhibited after a 1-hr exposure. At higher concentrations or for longer exposure times, DNA polymerase alpha was most sensitive to inhibition with greater than 60% of the activity being inhibited by 25 microM mercuric acetate after a 15-min exposure. There was no inhibition of DNA polymerase beta or uracil-DNA glycosylase activities in cells exposed to 50 microM mercuric acetate for 90 min. In fact, there was a time- and dose-dependent activation of uracil-DNA glycosylase activity with maximum activation occurring in cells exposed to 50 microM mercuric acetate. The inhibition of dUTPase and DNA polymerase alpha activities and the activation of uracil-DNA glycosylase activity correlated with the induction of single-strand breaks in DNA by mercuric acetate and with the decrease in cell viability.
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PMID:In vivo effects of mercury (II) on deoxyuridine triphosphate nucleotidohydrolase, DNA polymerase (alpha, beta), and uracil-DNA glycosylase activities in cultured human cells: relationship to DNA damage, DNA repair, and cytotoxicity. 302 30


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