Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Repair of X-ray-induced single-strand breaks of DNA was studied in vitro using an exonuclease purified from mouse ascites sarcoma (SR-C3H/He) cells. X-ray-dose-dependent unscheduled DNA synthesis was primed by the exonuclease. Repair of X-ray-induced single-strand breaks in pUC19 plasmid DNA was demonstrated by agarose gel electrophoresis after incubating the damaged DNA with the exonuclease, DNA polymerase (Klenow fragment of DNA polymerase I or DNA polymerase beta purified from SR-C3H/He cells), four deoxynucleoside triphosphates, ATP and DNA ligase (T4 DNA ligase or DNA ligase I purified from calf thymus). The present results suggested that the exonuclease is involved in the initiation of repair of X-ray-induced single-strand breaks in removing 3' ends of X-ray-damaged DNA.
Carcinogenesis 1990 Jul
PMID:Repair of X-ray-induced single-strand breaks by a cell-free system. 237 79

To establish an in vitro system for studying DNA repair, bleomycin-induced unscheduled DNA synthesis in permeable HeLa cells was investigated. Permeable HeLa cells were incubated at 0 degree C for 60 min with 0.11 mM bleomycin, washed to remove free bleomycin and assayed for DNA synthesis. Optimum [3H]deoxythymidine monophosphate incorporation occurred at pH 7.6-8.0 (adjusted at 20 degrees C with Tris-HCl buffer), 3-6 mM MgCl2, 40-60 mM NaCl, and 2.5-5 mM ATP in the presence of four deoxynucleoside triphosphates. The unscheduled nature of DNA synthesis in bleomycin-pretreated permeable cells was confirmed by the BrdUMP density shift technique. Exonuclease III sensitivity of repaired DNA was measured to determine whether or not the completion of repair patches and ligation occurred in bleomycin-pretreated permeable cells. Gap-filling and ligation were suggested to occur in the presence of ATP. Studies using the selective inhibitors (aphidicolin, 2',3'-dideoxythymidine 5'-triphosphate and N-ethylmaleimide) for DNA synthesis showed that DNA polymerases alpha and beta were involved in the repair process. Inhibitor studies suggested that DNA polymerase alpha plays a preferential role in repair label in the intranucleosomal region of nuclear chromatin and DNA polymerase beta in the completion of repair patches in bleomycin-pretreated permeable cells.
Carcinogenesis 1986 Jan
PMID:DNA repair synthesis in bleomycin-pretreated permeable HeLa cells. 241 38

A protein factor having exonucleolytic activity on bleomycin-damaged DNA and providing priming sites for DNA polymerases existed in a DNA polymerase beta fraction partially purified by ion exchange chromatography from an extract of permeable mouse ascites sarcoma (SR-C3H/He) cells. The exonuclease was separated from DNA polymerase beta by single-stranded DNA-cellulose chromatography, and partially characterized. The enzyme is suggested to be involved in the initial step of repair of bleomycin-damaged DNA in removing 3' ends (3'-phosphoglycolate termini) of bleomycin-damaged DNA.
Carcinogenesis 1988 Dec
PMID:An exonuclease possibly involved in the initiation of repair of bleomycin-damaged DNA in mouse ascites sarcoma cells. 246 Dec 64

Isolated trout liver cells were treated with lysolecithin to produce an in situ system for characterizing DNA repair in teleosts. In this preparation, the integrity of the plasma membrane is altered, nuclei remain intact, and the concentrations of dNTPs and nucleotide analogs, which normally do not penetrate intact plasma membranes, can be controlled. Following lysolecithin treatment, 50% of the total cellular protein and nearly 75% of total lactate dehydrogenase activity was released from the liver cells. Microscopic examination indicated that the integrity of the plasma membrane of trout hepatocytes was disrupted by lysolecithin; however, smaller nonhepatocytic liver cells were resistant to the disrupting effects of this detergent. Bleomycin induced DNA repair synthesis in lysolecithin-treated cells, as demonstrated by CsCl gradient analysis of 5-bromo, 2'-deoxyuridine, 5'-triphosphate-labeled DNA. Optimal conditions for bleomycin-induced DNA repair synthesis in lysolecithin-treated trout liver cells were considerably different from that in lysolecithin-treated mammalian cells. Bleomycin-induced DNA repair synthesis was lower in lysolecithin-treated trout liver cells than in lysolecithin-treated mammalian cells at identical concentrations of 2'-deoxyribonucleoside, 5'-triphosphates (dNTPs), suggesting the decreased sensitivity of trout cells in unscheduled DNA synthesis assays can be attributed to factors other than differences in dNTP pools. Bleomycin-induced DNA repair synthesis in trout hepatocytes was shown to be very sensitive to inhibition by 2', 3'-dideoxythymidine, 5'-triphosphate and was resistant to inhibition by cytosine arabinoside, 5'-triphosphate, butylphenyldeoxyguanosine, 5'-triphosphate and aphidicolin. These observations indicate repair of bleomycin-induced DNA damage in trout cells occurs through a mechanism similar to that in mammalian cells, utilizing DNA polymerase beta.
Carcinogenesis 1989 Jun
PMID:DNA repair synthesis in isolated rainbow trout liver cells. 272 Sep 10

The ability of Klenow polymerase I, phage T7 polymerase (Sequenase), human polymerase alpha, and human polymerase beta to synthesize past (bypass) O6-methylguanine (O6-meG) lesions was studied in the presence of MgCl2 and MnCl2. An end-labeled 16-mer primer was annealed to the 3' end of gel-purified oligodeoxyribonucleotide templates (45-mers), each containing a single O6-meG in place of one G in the sequence -G1G2CG3G4T-. Extension products were analyzed by denaturing polyacrylamide gel electrophoresis and autoradiography. A fraction of the products extended by Klenow fragment terminated either opposite or one base before O6-meG located at sites 1 and 3. Termination occurred primarily one base before O6-meG located at sites 2 and 4. The remaining fractions that bypassed the lesions represented full-length product. In control reactions, the O6-meG-containing templates were annealed with complementary 45-mers, repaired with O6-alkylguanine DNA-alkyltransferase, annealed with an excess of labeled primer, and extended by Klenow fragment. Full-length extension of > 90% was observed with each template. Primer extension past O6-meG by DNA polymerase alpha and Sequenase was partially blocked in a manner which varied with the site of O6-meG in the template while primer extension by DNA polymerase beta was completely blocked (< 2% full length extension) with O6-meG at sites 1-4. Substitution of MnCl2 for MgCl2 in the reaction mixture greatly increased the bypass of O6-meG by Klenow fragment and DNA polymerase alpha but not Sequenase or DNA polymerase beta. The increased ability of Klenow fragment to bypass O6-meG in the presence of MnCl2 was found to result from an increased incorporation of G (O6-meG at sites 1 and 2) and A (O6-meG at sites 1, 2, and 3) opposite the lesion. The results indicate that O6-meG can block in vitro polymerization by several DNA polymerases and are consistent with the observed cytotoxic effects of methylating agents on mammalian cells.
Carcinogenesis 1995 Aug
PMID:O6-methylguanine-induced replication blocks. 763 3

Recently, evidence has accumulated that mutations in DNA repair genes might be associated with certain steps in carcinogenesis. The DNA polymerase beta gene is one of the DNA repair genes, and mutations in it have been detected in 83% of human colorectal cancers. To assess the involvement of polymerase beta gene mutations in the development of human prostate cancers, we performed sequence analyses of human DNA samples. Unexpectedly, we found six regions that were polymorphic. This information should be taken into consideration at the time of sequence analysis of the DNA polymerase beta gene.
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PMID:Polymorphisms in the human DNA polymerase beta gene. 770 33

DNA polymerase beta is a nuclear protein essential to DNA repair in mammalian cells. A high frequency of mutations in this gene has been reported in colorectal cancers. To clarify the tumorigenesis steps of human prostate cancers in the molecular basis, we examined the entire coding region of the human DNA polymerase beta gene in human prostate cancer tissues using polymerase chain reaction, single-strand conformational polymorphism analysis of RNA, and sequencing analysis. Consequently, we detected DNA polymerase beta gene mutations in 2 of 12 cases (17%). The first case is an A to G transition at nucleotide 893, resulting in a substitution of the amino acid from tyrosine to cysteine. In the second case, we found an A to G transition at nucleotide 305, a T deletion at nucleotide 569, and an A insertion into the 6 repeats of A from nucleotide 612 to 617. This T deletion shifted the subsequent reading frame and resulted in the premature termination at codon 163 instead of 336. The two cases were advanced grade and stage. Present results suggest that polymerase beta gene mutations, although they occurred at relatively low frequency, are involved in certain cases of human prostate carcinogenesis.
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PMID:DNA polymerase beta gene mutation in human prostate cancer. 818 60

Formation of single strand breaks in nuclear DNA induced by hepatocarcinogens aflatoxin B1 and N-nitrosodimethylamine was observed to be more pronounced in rats maintained on a riboflavin-deficient diet compared to that on a normal diet. This increased damage was reversed on riboflavin supplementation. The induction of repair enzymes poly(ADP-ribose) polymerase, DNA polymerase beta and DNA ligase was significantly higher in riboflavin-deficient rats following DNA damage caused by the administration of carcinogens. Riboflavin supplementation brought down the induction to the levels found in rats maintained on normal diet. Since damage to DNA and its altered repair may relate to carcinogenesis, modulation of these parameters by riboflavin suggests a potential chemopreventive role of this vitamin.
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PMID:Modulation of carcinogen-induced DNA damage and repair enzyme activity by dietary riboflavin. 855 99

Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair-defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25-19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force.
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PMID:Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors. 869 23

The effect of different vitamin A status on events following DNA damage by hepatocarcinogens was investigated in rats. Formation of single-strand breaks in nuclear DNA induced by aflatoxin B1 and N-nitrosodimethylamine was observed to be more pronounced after vitamin A-deficiency. This enhanced damage was reversed upon vitamin A supplementation. Subsequent to DNA damage, the induction of repair enzymes poly(ADP-ribose) polymerase, DNA polymerase beta and DNA ligase was found to be significantly higher in vitamin A-deficient rats. Vitamin A supplementation brought down the induction to the levels found in rats maintained on normal diet. Vitamin A thus may control carcinogenesis by manipulating molecular events at the initiation stage.
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PMID:Effect of different vitamin A status on carcinogen-induced DNA damage and repair enzymes in rats. 872 17


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