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:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In studies on bacteria, the excision repair of UVR-induced DNA base damage has been divided into two major pathways on the basis of physiologic requirements and genetic control. The major pathway requires a functional polA+ gene, does not need complete growth medium, is largely error free, and produces short patches during repair. The second pathway requires complete growth medium and functional recA+, recB+, recC+, lexA+, uvrD+, and polC+ genes, is mutagenic, and produces long patches during repair. A second type of ecision repair exists, in which the modified base is removed by a DNA glycosylase, and the chain is nicked by an apurinic (apyrimidinic) acid endonuclease. Subsequent events are presumed similar to the above excision repair process. The postreplication repair system has been divided into at least four distinct pathways, three of which depend on functional recB+, lexA+, and uvrD+ genes, and are error free. A fourth pathway depends on the above gene products but is blocked by postirradiation treatment with chloramphenicol, and may be the UV-inducible, error-prone, mutagenic pathway of repair ("SOS repair"). A possible fifth pathway is dependent on a functional recF+ gene and is independent of the recB+-dependent pathway. Mutagenesis is the result of error-prone DNA repair, and evidence is growing that carcinogenesis is also the result of error-prone repair. Therefore, a complete understanding of DNA repair is crucial to a complete understanding of the molecular basis of carcinogenesis.
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PMID:Multiple pathways of DNA repair and their possible roles in mutagenesis. 38 33

Two endonuclease activities in rat liver for damaged DNA were assayed. Double-stranded, covalently closed DNA from phage PM2 was damaged by either ultraviolet irradiation or by heating at acid pH, and used as substrate for endonucleases specific for ultraviolet DNA damage and for DNA apurinic sites, respectively. The levels of both enzyme activities in livers of normal rats were compared to levels in livers of rats fed N-2-acetylaminofluorene. At critical stages of the carcinogenic regimen levels of both endonuclease activities were normal. This, together with other data, suggests that depression of excision-repair of DNA damage does not take place during experimental carcinogenesis.
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PMID:Normal endonuclease activities for damaged DNA during hepatocarcinogenesis. 88 9

Chinese hamster V79 lung fibroblasts are sensitive to the toxic effects of chloroethylating agents such as mitozolomide (Mz) and express very low levels (less than 2 fmol/mg) of the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase (ATase). These cells were subjected to selection by treatment with serially increasing doses of Mz. After each dose, the surviving population was expanded and ATase activity was determined in cell extracts. ATase specific activity increased stepwise and in cells surviving selection at 120 micrograms/ml Mz had reached 430 fmol/mg protein: polyacrylamide gel electrophoresis and fluorography showed the size of the ATase as 25 kDa. Cytological examination of these cells showed the presence of double minute (DM) chromosomes (mean approximately 3/cell) but no obvious homogeneously staining regions. In cells grown in continuous culture without further selection no marked decrease in ATase activity or DM frequency was observed. Karyotype analysis and DNA profiling confirmed that the parent and selected cells were of the same origin with, in the latter case, the probable loss or gain of a single restriction endonuclease site. No major differences were seen in the intensity of hybridization signals following Southern analyses of DNA from control and Mz selected cells using the human ATase cDNA as a probe. These results indicate that the ATase gene is not amplified in the Mz selected cells and suggest that increased ATase activity is a consequence only of increased transcription or translation of the ATase gene.
Carcinogenesis 1992 Mar
PMID:Upregulation of O6-alkylguanine-DNA-alkyltransferase expression and the presence of double minute chromosomes in alkylating agent selected Chinese hamster cells. 131 99

The biological effects of the interaction of methoxyamine (MX) with apurinic/apyrimidinic (AP) sites produced in CHO cells by treatment with alkylating agents were examined. A decrease in cytotoxicity was observed after a 10 min treatment with the SN1 alkylating agents ethylnitrosourea (ENU), N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) and N-methyl-nitrosourea when MX was present in the culture medium. Furthermore MX reduced the number of mutations to 6-thioguanine resistance induced by ENU and ENNG and the number of sister chromatid exchanges induced by ENU. In contrast, no protective effect of MX on survival was observed after a 10 min treatment with the SN2 alkylating agents diethylsulfate (DES), ethyl methane sulfonate and methyl methane sulfonate. A 3 h exposure to MX abolished the protective effect of MX on ENU-induced cytotoxicity and increased the cytotoxicity of DES. In vitro studies with synthetic oligonucleotides containing a single AP site opposite a normal guanine or O6-methylguanine showed that MX inhibits the cleavage of AP sites by the CHO AP endonuclease(s). A model is proposed in which different DNA lesions are involved in AP site formation after treatment with SN2 or SN2 alkylating agents. The involvement of specific alkylation products in cytotoxicity and mutagenesis is also discussed.
Carcinogenesis 1992 Jan
PMID:Methoxyamine modification of abasic sites protects CHO cells from the cytotoxic and mutagenic effects of oxygen alkylation. 137 Jul 69

Monoacetyl-hydroxyaminoquinoline 1-oxide (Ac-HAQO) is a model of the ultimate form of the carcinogen 4-nitroquinoline 1-oxide and so it is useful to characterize its reactions with DNA. We find that Ac-HAQO produces one single-strand break (SSB) for every 60 adducts formed in a reaction with supercoiled DNA. The SSBs do not appear to be formed by a free radical reaction and they are distributed throughout the DNA molecule without regard to nucleotide specificity. Unique DNA fragments were reacted with Ac-HAQO. These substrates could not be degraded by the 3'-5' exonuclease action of T4 DNA polymerase unless they were first cleaved by a restriction endonuclease. This indicated that the ends of all the DNA molecules were blocked by adduct formation in spite of the low overall frequency of adducts per DNA molecule.
Carcinogenesis 1991 Jun
PMID:The reaction of acetyl-4-hydroxyaminoquinoline 1-oxide with DNA: quantitation of single-strand break formation and hyper-reactivity of DNA termini. 164 83

Oxygen radicals have been suggested to be involved in mutation/carcinogenesis. The C-8 position of guanine residues in DNA is hydroxylated to produce 8-hydroxyguanine (8-OH-Gua) in DNA in vitro by various oxygen radical producing agents. The formation of 8-OH-Gua was also observed in cellular DNA in vivo by radiation or oxygen radical forming carcinogens. The 8-OH-Gua residue in DNA is often misread in the position of 8-OH-Gua residue itself but also at neighboring residues next to 8-OH-Gua. When second guanine in codon 12 was specifically replaced with 8-OH-Gua and transferred to NIH3T3, the recipient cells were transformed to malignant cell type. E. coli was found to contain an endonuclease which specifically recognizes 8-OH-Gua residue and cleave DNA strand before and after the modified base. The data obtained imply that 8-OH-Gua formed in DNA in vivo is recognized as an abnormal modified base which, if not repaired, play a role in the mediation of oxygen radical-involved mutation/carcinogenesis.
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PMID:8-Hydroxyguanine, a DNA adduct formed by oxygen radicals: its implication on oxygen radical-involved mutagenesis/carcinogenesis. 165 61

The denV gene from bacteriophage T4 encodes a pyrimidine dimer-specific endonuclease that has the capacity to initiate excision repair of DNA. Cells from excision repair-deficient xeroderma pigmentosum (XP) patients are able to carry out excision repair initiated by the denV gene product and introduction of the denV gene into XP cells results in the partial restoration of colony-forming ability after irradiation with UV light. In this work we have constructed a helper-independent recombinant human adenovirus, Ad5denV, which contains the denV gene. A 1.9 kb cartridge consisting of the denV gene flanked by the long terminal repeat (LTR) promoter from Rous sarcoma virus (RSV) and the simian virus 40 (SV40) polyadenylation (poly A) splice signals, was inserted into the E3 region of an E3 deletion mutant (Ad5d1E3) of adenovirus type 5. Infection of human fibroblasts and other permissive human cells with Ad5denV resulted in lytic infection and expression of the denV gene was confirmed by primer extension of infected cell RNA. The ability of the denV gene to restore the DNA repair deficiency in XP fibroblasts was examined using host cell reactivation of viral structural antigen formation for UV-irradiated adenovirus. The control virus, Ad5VSV, was also a recombinant which contained the gene for vesicular stomatitis virus glycoprotein G inserted into the E3 region of Ad5d1E3. UV survival of Ad5denV was similar to that of Ad5VSV following infection of two normal fibroblast strains and a Cockayne syndrome fibroblast strain, CS7SE, from complementation group B. In contrast, UV survival of Ad5denV was significantly greater than that for Ad5VSV after infection of three unrelated XP fibroblast strains from complementation groups A, C and E. However, UV survival of Ad5denV in the XP fibroblasts did not reach levels obtained in normal fibroblasts, indicating that restoration of the XP defect was partial.
Carcinogenesis 1991 Feb
PMID:Construction of a recombinant adenovirus containing the denV gene from bacteriophage T4 which can partially restore the DNA repair deficiency in xeroderma pigmentosum fibroblasts. 170 21

Somatic alterations of the c-Ha-ras gene were examined in 21 Japanese patients with hepatocellular carcinoma. Restriction endonuclease analysis by double digestion with MspI and HpaII revealed that DNAs from two of 21 hepatocellular carcinoma tissues were affected by nucleotide substitution at the twelfth amino acid coding sequence of the c-Ha-ras gene. DNAs from cirrhotic noncancerous liver tissue, but not leukocytes, of one of these patients possessed the mutation, whereas DNAs from noncirrhotic liver tissue and leukocytes of the other patient did not. In one of the nine patients harboring heterozygosity for c-Ha-ras-related BamHI-fragments, the loss of one allele was demonstrated as a somatic change not only in DNA from the tumor tissue but also in DNA from the cirrhotic nontumorous tissue. In two of the 19 patients comparatively examined for digestion patterns of c-Ha-ras locus with HpaII and MspI, extensive methylation was observed as a somatic modification in both DNAs from the tumor and the cirrhotic nontumorous tissues. These results thus indicate that the genetic lesions affecting the c-Ha-ras gene do occur in human hepatocellular carcinoma and probably serve as one of the multiple steps in the process of hepatic carcinogenesis.
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PMID:Point mutation, allelic loss and increased methylation of c-Ha-ras gene in human hepatocellular carcinoma. 184 46

Previous studies have demonstrated that the mouse c-Harvey ras proto-oncogene (c-Ha-ras) promoter sequences are GC rich and contain several potential transcription factor SP1 binding sites. We investigated the endonuclease hypersensitivity of this region in nuclei in vitro and whole mouse tissues in vivo and identified a very strong, ubiquitous hypersensitive site covering the proximal promoter sequences. Footprint protection studies using nuclear extracts from various cell types including fibroblasts, erythroid cells, and both normal and transformed epithelial cells revealed a consistent protein-binding pattern. Five protein binding sites were observed, four of which correlated with potential SP1 binding sites. Competition experiments using an oligonucleotide corresponding to a consensus SP1 binding site confirmed that these sequences were indeed bound by the SP1 (or SP1-like) trans-acting factor. In addition, no differences were observed between the footprint patterns obtained using extracts from cells of different lineages or between normal and transformed epithelial cells carrying activated ras genes. The controlling elements responsible for differential c-Ha-ras transcription between cell types or at different stages of carcinogenesis therefore probably lie in other regions of the gene.
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PMID:Structural analysis of the mouse c-Ha-ras gene promoter. 204 51

pBR322 plasmid DNA, randomly substituted with arylamine moieties, was introduced into Escherichia coli Uvr endonuclease deficient strains. Plasmid survival was determined by selection in the presence of ampicillin. Modification of plasmid DNA with N-acetoxy-N-trifluoroacetylaminobiphenyl yielded primarily N-(deoxyguanosin-8-yl)-4-aminobiphenyl residues. Reaction of DNA with N-acetoxy-N-acetylaminobiphenyl produced only N-(deoxyguanosin-8-yl)-4-acetylaminobiphenyl adducts. The aminobiphenyl (ABP) and acetylaminobiphenyl adducts reduced the ability of the plasmid DNA to transform E. coli to approximately the same extent in a wild-type strain. In uvrA, uvrB and uvrC, i.e. Uvr endonuclease deficient strains, both adducts produced equivalent decreases in survival, however, the reduction in survival was much more pronounced in the uvr- cells than in the wild-type strain. A similar pattern of toxicity was observed with plasmids carrying N-(deoxyguanosin-8-yl)-2-acetylaminofluorene adducts, although the acetylaminofluorene adduct was approximately 5-fold more effective in reducing the biological activity of the plasmid. In contrast, the deacetylated aminofluorene (AF) lesion, N-(deoxyguanosin-8-yl-2-aminofluorene, exhibited relatively little effect on plasmid survival in uvrA and uvrB cells as compared to the wild-type strain, even though the survival of both ABP and AF adducts was essentially similar in the uvrC and wild-type strains. These data demonstrate that (i) both the deacetylated and acetylated lesions are subject to repair by the Uvr endonuclease complex, and (ii) the presence of the N-acetyl group is not the sole determinant of the differential effects of arylamine adducts in uvr cells. These observations provide indirect evidence that both the N-acetyl and aryl moieties of these adducts alter the conformation of DNA.
Carcinogenesis 1990 Apr
PMID:Comparative survival of aminobiphenyl- and aminofluorene-substituted plasmid DNA in Escherichia coli Uvr endonuclease deficient strains. 218 16


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