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)

Isolated rat pancreatic polynucleosomes were poly(ADP-ribosylated) with purified calf thymus poly(ADP-ribose) polymerase. A time course study was performed using an NAD concentration of 200 microM and changes in nucleosomal structure were investigated by means of electron microscopy visualization and sedimentation velocity determinations. In parallel, analyses of histone H1 poly(ADP-ribosylation) and determinations of DNA polymerase alpha activity on ADP-ribosylated polynucleosomes were done at different time intervals. A direct kinetic correlation between ADP-ribose incorporation, polynucleosome relaxation amd histone H1 hyper-ADP-ribosylation was established. In addition, DNA polymerase alpha activity was highly stimulated on ADP-ribosylated polynucleosomes as compared to control ones, suggesting increased accessibility of DNA to enzymatic action. Because of the strong evidence implicating histone H1 in the maintenance of higher-ordered chromatin structures, the present study may provide a basis for the interpretation of the involvement of the histone H1 ADP-ribosylation reaction in DNA rearrangements during DNA repair, replication or gene expression.
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PMID:Time course of polynucleosome relaxation and ADP-ribosylation. Correlation between relaxation and histone H1 hyper-ADP-ribosylation. 391 19

Incubation of DNA polymerase alpha, DNA polymerase beta, terminal deoxynucleotidyl transferase, or DNA ligase II in a reconstituted poly(ADP-ribosyl)ating enzyme system markedly suppressed the activity of these enzymes. Components required for poly(ADP-ribose) synthesis including poly(ADP-ribose) polymerase, NAD+, DNA, and Mg2+ were all essential for the observed suppression. Purified poly(ADP-ribose) itself, however, was slightly inhibitory to all of these enzymes. Furthermore, the suppressed activities of DNA polymerase alpha, DNA polymerase beta, and terminal deoxynucleotidyl transferase were largely restored (3 to 4-fold stimulation was observed) by a mild alkaline treatment, a procedure known to hydrolyze alkaline-labile ester linkage between poly(ADP-ribose) and an acceptor protein. All of these results strongly suggest that the four nuclear enzymes were inhibited as a result of poly(ADP-ribosyl)ation of either the enzyme molecule itself or some regulatory proteins of these enzymes.
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PMID:Inhibition of DNA polymerase alpha, DNA polymerase beta, terminal deoxynucleotidyl transferase, and DNA ligase II by poly(ADP-ribosyl)ation reaction in vitro. 392 Oct 27

Evidence is presented to show that ADP-ribosylation of nuclear proteins by poly(ADP-ribose) polymerase enhances template-primer activity of HeLa cell nuclear DNA. We used Escherichia coli DNA polymerase I (EC 2.7.7.7; DNA nucleotidyltransferase) as an exogenous probe of nuclear DNA status. Neither NAD nor free poly(ADP-ribose) acts directly on the bacterial enzyme. The stimulation is specific for formation of ADP-ribosylated proteins and is not a generalized polyanion or nucleotide effect on chromatin. The release of template restriction is proportional to the capacity of a given cell line to synthesize poly(ADP-ribose); both the stimulation and poly(ADP-ribose) formation are coordinately proportional to NAD concentration. Binding studies with DNA polymerase indicate exposure or generation of additional 3'-OH primer sites due to ADP-ribosylation in intact nuclei. With intact cells, there appears a correlation among growth, physiological template restriction, and the above effects of ADP-ribosylation.
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PMID:Poly(ADP-ribose): release of template restriction in HeLa cells. 437 Feb 71

Human lung cancers of distinct histology exhibit different responses to radiation therapy in vivo. For examination of the basis of this phenomenon, the radiation survival curves and levels of relevant enzymes were determined in 16 lung cancer cell lines derived from tumors of different histology. These included lines from 5 adenocarcinomas, 7 small cell tumors, 3 variant small cell tumors, and 1 large cell tumor. These findings were compared to those obtained with the use of a normal skin fibroblast cell line. Whether cloned in liquid culture or soft agarose, cell lines had similar radiation survival curves. These curves were consistent with the apparent in vivo radiation responsiveness of the tumors. Although considerable heterogeneity in radiation survival curves was observed among the cell lines, cells from large cell lines and small variant lines had pronounced shoulders and extrapolation numbers (n) from 5.6 to 14. In contrast, cells from small cell lines and adenocarcinoma cell lines were more "sensitive" (-n values of 1-3.3). In these cell lines, levels of DNA polymerase beta, glutathione (GSH), GSH transferase, GSH reductase (NAD(P)H), gamma-glutamyltransferase did not correlate with radiation parameters of sensitivity. DNA polymerase beta and GSH levels were, however, higher than those in a line of normal skin fibroblasts. These cell lines may be useful in identifying the basis of the variable responsiveness of human lung cancer cells to ionizing radiation.
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PMID:Heterogeneity in the radiation survival curves and biochemical properties of human lung cancer cell lines. 614 44

This review discusses the potential relationships between ADP-ribosylation reactions, DNA repair, cell differentiation, and cancer. ADP-ribosylation of chromatin proteins has been shown to participate in DNA excision repair in all nucleated cells. ADP-ribosylation of chromatin proteins is catalysed by nuclear ADP-ribosyl transferase (ADPRT). This enzyme is entirely dependent on DNA for its activity because it has an absolute requirement for ends or nicks in double-stranded DNA. Exposure of cells to small alkylating agents or to radiation causes a fall in cellular NAD+ levels due to a transient activation of ADPRT and a consequent ADP-ribosylation of chromatin proteins. Inhibitors of ADPRT retard DNA strand-rejoining induced by radiation or by small alkylating agents; such inhibition has at least two biological consequences; a synergistic potentiation of cytotoxicity and an enhancement of sister chromatid exchanges and chromosomal aberrations. No species differences have yet been reported; there are variations between cell types and between different damaging agents. The enzyme inhibitors do not block early steps in DNA repair, and repair synthesis does not require ADPRT activity. DNA damage increases the activity of both DNA polymerase beta and DNA ligase II. The activation of DNA ligase II can be blocked by ADPRT inhibitors; presumably ADPRT activity is required for the activation of DNA ligase II. A plausible molecular explanation for the function of ADPRT in DNA repair is that ADPRT regulates the activity of DNA ligase II, the "non-replicative" ligase. In addition to its function in DNA repair, ADPRT is an obligatory requirement in certain categories of cell differentiation. Inhibitors of ADPRT and nicotinamide starvation both reversibly block cell differentiation. We suggest that a similar mechanism to that of DNA repair may be involved because we observe 100 to 300 single-strand DNA breaks during the cytodifferentiation of primary chick myoblasts. These breaks are not due to a general deficiency in DNA repair. I suggest that in certain categories of cell differentiation there are rearrangements or transpositions within the mammalian genome, and that ADP-ribosylation reactions have a general function to be sensitive to DNA breaks and to regulate subsequent DNA ligation in DNA repair, in DNA recombination, in sister chromatid exchanges, in chromosome aberrations, in gene rearrangements, in transpositions and in certain categories of cell differentiation. The relevance of these observations and ideas to cancer is discussed.
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PMID:ADP-ribosylation, DNA repair, cell differentiation and cancer. 631 41

A cell-free extract from blue-green alga Anacystis nidulans contains enzymes which repair in vitro the transforming activity of gamma-irradiated Bacillus subtilis DNA. The level of restoration of the transforming activity depends on the protein concentration in the reaction mixture, the duration of incubation and on the dose of irradiation. The repair of gamma-induced lesions is most efficient in the presence of magnesium ions, NAD and ATP. The present data indicate that the repair of transforming DNA is performed with the participation of DNA polymerase and polynucleotide ligase which function in the cell-free extract of algae.
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PMID:[In vitro repair of gamma-irradiated transforming Bacillus subtilis DNA by extracts of blue-green algae]. 680 46

Gamma-irradiation of Escherichia coli cells made permeable to deoxynucleoside triphosphates (dNTP) by toluene induces a repair-type DNA synthesis. As previous studies have shown ATP stimulates this DNA synthesis; we studied the mechanism of the ATP effect by analyzing the kinetics of nucleotide incorporation at various dNTP concentrations. The V values of the DNA repair synthesis rise with increasing dose (0-50 Gy); nonirradiated cells showed a negligible nucleotide incorporation. The apparent Michaelis constant KM for dNTP in the assay was 83-143 microM and the value was much higher than for a DNA polymerase reaction in vitro. ATP stimulated the DNA synthesis with concomitant decrease of KM yet unchanged V values. Similar results were obtained with a rec BC strain. We propose that the ATP effect is due to a greater affinity of dNTPs to the DNA polymerase, possibly by a stabilisation of the structural integrity of the complex DNA with repair enzymes. Activation of exonucleases by ATP could be excluded. Addition of NAD to the reaction mixture inhibits the DNA synthesis possibly by activation of ligase which closes the nicks in the DNA strand.
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PMID:Mechanism of the ATP effect in the DNA repair synthesis of gamma-irradiated Escherichia coli cells. 698 3

The effect of inhibition of poly(ADP-ribose) polymerase (PARP) on the growth arrest and cell killing induced by N-methyl-N-nitrosourea (MNU) was studied in L929 fibroblasts. Depletion of NAD and ATP preceded the cell killing by a 1-h exposure to 10 or 15 mM MNU. 3-Aminobenzamide (ABA), an inhibitor of PARP, spared the depletion of NAD and ATP and prevented the cell killing. With 5 mM MNU, a depletion of NAD was promptly reversed, and there was no loss of ATP and no cell death. Aphidicolin, a DNA polymerase inhibitor, prevented the restoration of NAD, with resulting depletion of ATP and death of the cells, effects that were prevented by ABA. Azide together with 2-deoxyglucose depleted ATP, followed by a loss of NAD and cell death, changes that occurred in the absence of DNA single strand breaks (DNA SSB). ABA prevented the depletion of NAD, but not that of ATP, nor the cell killing. MNU (2.5 mM) inhibited cell growth without effect on the viability of the cells. ABA potentiated the cell growth inhibition. Thus, inhibition of PARP potentiates cell growth inhibition by limiting DNA repair mechanisms. Alternatively, inhibition of the DNA repair response to more extensive DNA damage prevents cell killing. The ATP depletion caused by poly(ADP-ribosyl)ation, rather than DNA SSB and the loss of NAD, is the more critical event in the cell killing.
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PMID:Growth inhibition and cell killing by N-methyl-N-nitrosourea: metabolic alterations that accompany poly(ADP-ribosyl)ation. 778 36

A model for eukaryotic DNA damage repair is proposed in which poly(ADP-ribose) polymerase(NAD+ ADP-ribosyl transferase, EC 2,4,2,30) plays an important role. In this model, poly(ADP-ribose) polymerase regulates transcription of genes that are induced by DNA-damaging agents. This transcriptional regulation results from poly(ADP-ribosyl)ation and inactivation of DNA sequence-specific regulatory proteins such as silencer element-binding proteins, thereby inducing transcription of DNA polymerase beta, which is a DNA repair enzyme in higher eukaryotes. Poly(ADP-ribose) polymerase has a number of similarities to RecA in Escherichia coli. Therefore, the genes related to DNA damage repair in higher eukaryotes are proposed to form a "poly(ADP-ribose) polymerase regulatory network" similar to the "SOS regulatory network" in E. coli.
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PMID:Speculations on the roles of ADP-ribosyl transferase based on analogies between RecA and poly(ADP-ribose) polymerase. 824 22

Computer analysis of a conserved domain, BRCT, first described at the carboxyl terminus of the breast cancer protein BRCA1, a p53 binding protein (53BP1), and the yeast cell cycle checkpoint protein RAD9 revealed a large superfamily of domains that occur predominantly in proteins involved in cell cycle checkpoint functions responsive to DNA damage. The BRCT domain consists of approximately 95 amino acid residues and occurs as a tandem repeat at the carboxyl terminus of numerous proteins, but has been observed also as a tandem repeat at the amino terminus or as a single copy. The BRCT superfamily presently includes approximately 40 nonorthologous proteins, namely, BRCA1, 53BP1, and RAD9; a protein family that consists of the fission yeast replication checkpoint protein Rad4, the oncoprotein ECT2, the DNA repair protein XRCC1, and yeast DNA polymerase subunit DPB11; DNA binding enzymes such as terminal deoxynucleotidyltransferases, deoxycytidyl transferase involved in DNA repair, and DNA-ligases III and IV; yeast multifunctional transcription factor RAP1; and several uncharacterized gene products. Another previously described domain that is shared by bacterial NAD-dependent DNA-ligases, the large subunits of eukaryotic replication factor C, and poly(ADP-ribose) polymerases appears to be a distinct version of the BRCT domain. The retinoblastoma protein (a universal tumor suppressor) and related proteins may contain a distant relative of the BRCT domain. Despite the functional diversity of all these proteins, participation in DNA damage-responsive checkpoints appears to be a unifying theme. Thus, the BRCT domain is likely to perform critical, yet uncharacterized, functions in the cell cycle control of organisms from bacteria to humans. The carboxyterminal BRCT domain of BRCA1 corresponds precisely to the recently identified minimal transcription activation domain of this protein, indicating one such function.
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PMID:A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. 903 68


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