Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in metal carcinogenesis are comprehensively reviewed, including (a) epidemiological and clinical aspects, (b) carcinogenesis bioassays, (c) bacterial mutagenesis, (d) mammalian cell mutagenesis, (e) chromosomal damage, (f) mammalian cell transformation, (g) microsomal metabolism, (h) DNA strandbreaks and crosslinks, (i) DNA polymerase infidelity, (j) RNA strand initiation, and (k) helical transition of B-DNA to Z-DNA. Based upon these observations, several hypotheses are proposed for the molecular pathogenesis of carcinogenesis by metal compounds. These hypotheses are amenable to experimental test by existing techniques of molecular biology.
 ...
PMID:Recent advances in metal carcinogenesis. 620 Nov 24

Terminal deoxynucleotidyl transferase (TdT) was used to prepare copolymers of dA and 1,N6-ethenodeoxyadenosine (epsilon dA). When used as templates for Escherichia coli DNA polymerase I (Pol I) and compared with poly (dA), normal dTTP incorporation was not significantly affected by the presence of 7% epsilon dA. dGTP misincorporation was only slightly increased and occurred about once for every 500 epsilon dA residues. The error-prone polymerase from avian myeloblastosis virus (AMV reverse transcriptase) increased this error rate 5- to 20-fold to a maximum of 1 dG/25 epsilon dA. No dCTP misincorporation was detected with either polymerase. In transcription with E. coli DNA-dependent RNA polymerase, no errors were revealed by nearest neighbor analysis. Poly (dA) treated with chloroacetaldehyde under conditions producing the same proportion of epsilon dA (without the hydrated form) as the synthesized template behaved in the same manner with a similar low level of misincorporation of dG. Such treatment of alternating poly d(A-T) caused structural changes indicative of crosslinks but did not alter its template properties. Increasing the amount of epsilon dA in either synthesized or modified polymers greatly decreased the template activity without increasing the error rate. It is suggested that epsilon dA generally does not prevent dT incorporation but behaves as a bulky lesion which is bypassed. In contrast to the low mutagenic efficiency of epsilon dA, O4-methyldeoxythymidine (m4dT), in copolymers with dA, directed the misincorporation of 1 dG/12 m4dT with Pol I and 1 dG/3 m4dT with reverse transcriptase. Nearest neighbor analysis of transcripts showed the incorporation of 1 dG/12 m4dT. These data are in agreement with the previous reported mutagenicity of m4dT in alternating poly d(A-T, m4T).
Carcinogenesis 1984 Sep
PMID:Assessment of mutagenic efficiency of two carcinogen-modified nucleosides, 1,N6-ethenodeoxyadenosine and O4-methyldeoxythymidine, using polymerases of varying fidelity. 620 83

We investigated, in a cloned hamster tracheal epithelial cell line HTE-B, the effects of inhibitors of DNA topoisomerase, novobiocin and nalidixic acid; of DNA polymerase, 1-beta-arabinofuranosylcytosine (ara-C) and 2',3'-dideoxythymidine; of ribonucleotide reductase, hydroxyurea; and of poly(ADP-ribose)synthetase, 3-aminobenzamide, upon the removal of benzo[a]pyrene adducted to DNA [B[a]P--DNA]. A substantial reduction in the rate of removal of the polycyclic hydrocarbon-adducts occurred when nalidixic acid was added to the HTE-B cells that had been previously incubated with B[a]P for 8 h. Novobiocin produced a similar, but less marked, effect. The rate of disappearance of the individual B[a]P--DNA adducts was measured by analysis of the h.p.l.c. profiles. Of the 5 major adducts observed under the h.p.l.c. conditions, 4 were reduced in control cells to 30% of the original levels by 24 h after removal of the B[a]P from the medium; adduct 5 was almost completely removed. In the presence of nalidixic acid, during the 24 h repair period, only the removal of adduct 5 was unimpaired; the removal of the other 4 adducts was significantly retarded. On the other hand, 3-aminobenzamide addition did not affect the rate of removal of B[a]P--DNA adducts from the HTE-B cells. We employed the combinations of ara-C and dideoxythymidine or ara-C and hydroxyurea to allow the accumulation of single strand breaks after incubation of the HTE-B cells with B[a]P. These breaks were assayed by alkaline elution analysis. Inclusion of these inhibitors during the 2 h after removal of the B[a]P from the medium resulted in the accumulation of 4-5 single strand breaks/10(10) daltons of HTE-B DNA. This compares with a minimum estimate of the number of adducts removed during this period of 3 adducts/10(7) daltons. This discrepancy may indicate that the majority of lesions are not repaired by a pathway sensitive to polymerase inhibitors. In the presence of 3-aminobenzamide, we routinely observed a 10% increase in the alkaline elution of the DNA obtained from B[a]P-treated cells (1-2 breaks/10(10) daltons). Our results indicate that an excision repair process may be involved in the removal of at least some of the B[a]P-induced damage to DNA. However, the repair of the multiple adducts is complex and may involve pathways other than classical excision repair.
Carcinogenesis 1984 Feb
PMID:The influence of inhibitors on the repair of benzo[a]pyrene-damaged DNA in hamster tracheal epithelial cells. 632 Oct 50

Poly(dC,3- MedC ) has been synthesised and used as a template to compare the miscoding properties of 3-methylcytosine (3-MeC) during DNA and RNA synthesis. Although 3-MeC was promutagenic with the RNA polymerase incorporating both AMP and UMP in the ratio of approximately 5:1 (agreeing with results reported by earlier workers) no non-complementary nucleotide incorporation was observed with DNA polymerase I. The results show that 3-MeC, which is a strong inhibitor of DNA synthesis, is only promutagenic with the less accurate RNA polymerase and that the reported differences in promutagenicity for this modified base with the two nucleotide polymerising enzymes arise from different specificities for the two enzymes.
Carcinogenesis 1984 May
PMID:Differences in the promutagenic nature of 3-methylcytosine as revealed by DNA and RNA polymerising enzymes. 637 42

Ascorbate-Cu2+ shows considerable cytotoxicity for human melanoma cells at a dose which has very little effect on human fibroblasts. Ascorbate itself inhibits DNA synthesis in melanoma cells but does not fragment the parental DNA. However, the combined action of ascorbate-Cu2+ generates fragmentation of the parental DNA due to the induction of alkali-labile bonds in the DNA. In contrast, if DNA polymerase alpha is inhibited by aphidicolin prior to treatment with ascorbate-Cu2+ one cannot detect the fragmentation of the DNA. The generated fragments show a discrete appearance in agarose gel electrophoresis with a single-stranded size of approximately 5 kb. When fibroblasts were analyzed using the same experimental protocol it was not possible to detect the fragmentation of the DNA.
Carcinogenesis 1983
PMID:Ascorbate-Cu2+ fragments melanoma DNA but not fibroblast DNA into a discrete DNA population. 640 86

Excision repair of u.v. damage in human fibroblasts is more sensitive to inhibitors of DNA polymerase alpha (cytosine arabinoside, aphidicolin) than to an inhibitor of polymerase beta (dideoxythymidine), which indicates a greater role in repair for polymerase alpha than for polymerase beta. These inhibitors all generate shortened patches with free 3' termini; the detailed structure of these patches was investigated in permeable cells or isolated nuclei by degradation of DNA with exonuclease III and by resynthesis with DNA polymerase I (Klenow fragment) and T4 DNA ligase. The structure of the shortened patches appears to be a short stretch of DNA synthesized in the 5'----3' direction within a longer single-strand gap. The single-strand gap ahead of the 3' terminus can be bridged only by the combined action of polymerase and ligase. This structure implies that excision must involve removal of an oligonucleotide or widening of a gap by 5'----3' exonuclease action to produce a single-strand region wide enough to be a substrate for polymerase alpha. There is no evidence for structures generated by nick translation or strand displacement.
Carcinogenesis 1984 Mar
PMID:Completion of excision repair patches in human cell preparations: identification of a probable mode of excision and resynthesis. 642 5

The lethality of N-methyl-N-nitrosourea (MNU) to mouse L1210 cells, as determined by colon forming ability, was potentiated 2.8 fold by the addition of 1 mM 5'-methylnicotinamide (5MeN). When 5MeN was present throughout the expression and selection of 6-thioguanine resistant mutants, the MNU-induced mutation frequency was reduced in duplicate experiments from 15.6 and 12.0 to 7.0 mutants per 10(4) survivors per mM MNU. At the same level of survival, cells treated with 5MeN had approximately 12 times fewer mutants than untreated cells. The rate of removal of the promutagenic lesion O6-methylguanine from DNA was enhanced approximately 2-fold, whereas that of 7-methylguanine was unaffected by the incubation of MNU treated cells with 5MeN. Since 5MeN is a potent inhibitor of poly(ADP-ribose) polymerase, this may imply that in normal cells it is specific ADP-ribosylation of the repair enzyme causing the removal of O6-methylguanine, rather than a more general modification of chromatin structure, that limits the rate of repair of the promutagenic lesion. 5MeN also stimulated unscheduled DNA synthesis in MNU treated cells, implying that an earlier observation that 5MeN prevented rejoining of strand breaks induced by repair of alkyl lesions, probably resulted from inhibition of ligation and not the failure of DNA polymerase to replace bases removed by repair nucleases.
Carcinogenesis 1981
PMID:Effects of 5-methylnicotinamide on mouse L1210 cells exposed to N-methyl-N-nitrosourea: mutation induction, formation and removal of methylation products in DNA, and unscheduled DNA synthesis. 645 99

The activities of the DNA repair enzymes O6-methylguanine-DNA methyltransferase and uracil-DNA glycosylase, and the replicative enzyme DNA polymerase alpha, were measured in extracts of human fetal tissues at 18-20 weeks of gestation. In general, O6-methylguanine-DNA methyltransferase activities in fetal tissues were in the same range as in the corresponding adult tissues, except for fetal liver which had approximately 5-fold lower activity. Uracil-DNA glycosylase was, surprisingly, approximately 4-fold lower in fetal tissues compared with adult tissues. Since a critical factor in carcinogenesis may be the rate of repair relative to DNA replication, the activities of O6-methylguanine-DNA methyltransferase and uracil-DNA glycosylase were compared with the DNA polymerase alpha activity in the same extract. When expressed in this way, O6-methylguanine-DNA methyltransferase activity was lowest in liver and brain and 2- to 14-fold higher in kidney, lung, colon, stomach, small intestine and pancreas. The ratio of uracil-DNA glycosylase to DNA polymerase alpha varied less between different organs. These findings indicate that several fetal organs may be more sensitive than adult organs to some alkylating agents that are known to occur in the environment. Furthermore, the lower capacity of DNA repair is not restricted to repair of alkylation damage, since the activity of uracil-DNA glycosylase is also lower than in adult tissues.
Carcinogenesis 1983 Dec
PMID:Repair of premutagenic DNA lesions in human fetal tissues: evidence for low levels of O6-methylguanine-DNA methyltransferase and uracil-DNA glycosylase activity in some tissues. 665 68

DNA polymerases alpha and beta were treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The activities of the modified DNA polymerase were decreased and the degree of lowered activity varied with the template employed. However, no decrease in fidelity was observed in DNA synthesis by the MNNG-treated polymerases. It is suggested that direct modification of the DNA polymerase molecule by MNNG is not the cause of carcinogenesis.
 ...
PMID:Effect of N-methyl-N'-nitro-N-nitrosoguanidine on DNA polymerases alpha and beta in vitro. 665 82

Aphidicolin is a specific inhibitor of DNA polymerase alpha. Its influence of DNA repair has been studied in both normal and excision deficient xeroderma pigmentosum cells exposed to u.v. irradiation at 254 nm. Single strand DNA breaks accumulated in u.v. irradiated normal cells when the inhibitor was present. Such breaks were absent in both unirradiated normal cells and in u.v. irradiated excision efficient cells incubated with the compound. The data therefore indicate that aphidicolin prevents the rejoining of single strand breaks formed during the excision repair process and imply that DNA polymerase alpha is involved in the repair of DNA in human cells.
Carcinogenesis 1981
PMID:Aphidicolin: an inhibitor of DNA repair in human fibroblasts. 679 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>