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)

Further evidence for the preferential interaction of carcinogens with mitochondrial DNA (mtDNA) has been obtained. In rats treated with high doses of N-nitrosodimethylamine (NDMA) or N-nitroso-N-butylurea (NBU), hepatic mtDNA contains 1.4 times more O6-methyl-2'-deoxyguanosine (O6-MedG) or 2.3 times more O6-butyl-2'-deoxyguanosine (O6-BudG) than does nuclear DNA (nDNA). The kinetics of removal of O6-MeG from mtDNA and nDNA are similar at both high (20 mg/kg) and low (2 mg/kg) doses of NDMA, and the removal of O6-MeG can be increased by pretreating the animals with 2-acetylaminofluorene (AAF), indicating that O6-MeG is repaired in the mitochondrion by a mechanism similar to that which functions in the nucleus. In contrast, O6-BudG is removed very slowly from mtDNA and rapidly from nDNA, an observation which is consistent with the absence of a nucleotide excision mechanism in the mitochondrion and the repair of O6-BudG, predominantly by an excision mechanism, in the nucleus of mammalian cells. A 23-kd methyltransferase (MT) protein, similar to the one found in the nucleus, has been isolated from hepatic mitochondria and is present in mitochondria from which the outer membrane has been removed. It is suggested that O6-MeG, but not O6-BuG can be repaired from mtDNA by a MT protein that is nuclear encoded and transported across the mitochondrial membrane.
Carcinogenesis 1988 Feb
PMID:Repair of alkylated purines in the hepatic DNA of mitochondria and nuclei in the rat. 333 12

The short-term effects of a lipotrope-deficient (methyl-deficient) diet on tRNA and protein methyltransferase activities have been studied using pair-fed male Fischer rats. The activity of liver N2-guanine tRNA methyltransferase II (NMG2) of animals receiving the methyl-deficient diet (MDD) for 2 weeks was found to be elevated more than 2-fold. This is in agreement with the results of earlier experiments in which the animals were fed ad libitum. These data indicate that the effects of lipotrope-deficient diets on NMG2 activity observed in the earlier studies can be attributed to the nature of the diet, and not to differences in caloric intake. In the same pair-fed animals, very little effect of MDD on the activity of NMG2 of either brain or spleen was observed. In liver, the activity of one of the enzymes that catalyze protein methylation--protein methylase I (S-adenosyl-methionine: protein-arginine N-methyltransferase)--was significantly elevated in response to the lipotrope-deficient diet. In contrast, the activities of protein methylase II (S-adenosylmethionine: protein-carboxy-O-methyltransferase), from control and experimental animals did not differ significantly. Lipotrope-deficient diets are thus seen to induce, within a short period of time, selective changes in the activities of some, but not all, of the liver enzymes that catalyze the methylation of tRNA and protein.
Carcinogenesis 1988 May
PMID:Comparison of methyltransferase activities of pair-fed rats given adequate or methyl-deficient diets. 336 48

A modified Escherichia coli ada+ gene which encodes methyltransferase active on O6-methylguanine, but not methylphosphotriester residues in DNA has been introduced by transfection into Chinese hamster ovary cells. Expression of the altered Ada protein in these cells conferred resistance to methylating agents. However, in two independently derived cell lines, the relation between enzyme activity and the degree of protection was not quantitative. The molecular nature of the Ada protein fragment produced differed between the two cell lines. In addition, cell lines exhibiting increased resistance to N-methyl-N'-nitro-N-nitrosoguanidine have been derived from a cell line expressing the Ada protein methylphosphotriester repair function. The resistant cell lines expressed elevated levels of methylphosphotriester repair protein. However, this enhanced DNA repair activity was not responsible for the observed resistance.
Carcinogenesis 1988 Sep
PMID:The contribution of O6-methylguanine and methylphosphotriesters to the cytotoxicity of alkylating agents in mammalian cells. 340 62

The O6-methylguanine-DNA-methyltransferase activity was measured in rat hepatoma cells (H4 cells) at different times after N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methylmethane sulfonate (MMS) or ethylmethane sulfonate (EMS) treatment. Incubation with MNNG (10 microM) first depletes the methyltransferase activity, then the number of methyltransferase molecules per cell increases and reaches approximately 3-fold the constitutive level after 48 h. Incubations with MMS (0.5 or 1 mM) or with EMS (5 or 10 mM) do not modify or partially decrease the constitutive methyltransferase level. However, an enhancement of the activity is also observed after 48 h: the activity in 5- and 4-fold higher than the control value in MMS- and EMS-treated cells, respectively. The methyltransferase increase is due to de novo protein synthesis. It is not observed in cells constitutively lacking this protein. The data suggest that the O6-methylguanine (O6-meGua) repair capacity of H4 cells can be increased after a single treatment with alkylating agents, by a process different to the adaptive response.
Carcinogenesis 1987 Jan
PMID:The O6-methylguanine-DNA-methyltransferase activity of rat hepatoma cells is increased after a single exposure to alkylating agents. 380 98

Mer- human cells, which lack O6-methylguanine DNA methyltransferase activity, are extremely sensitive to alkylation induced killing, mutation and sister chromatid exchange. We have analyzed a Mer+, a Mer-, and a Mer- revertant HeLa cell line and found that the methyltransferase deficiency correlates with increased levels of mutation and sister chromatid exchange, but does not correlate with increased killing of Mer- HeLa cells by alkylating agents. Furthermore, we show that HeLa Mer- cells repair N-3-methylguanine and N-3-methyladenine just as efficiently as HeLa Mer+ cells.
Carcinogenesis 1987 Feb
PMID:DNA alkylation repair and the induction of cell death and sister chromatid exchange in human cells. 380 5

The effect of whole body ionising radiation from a linear accelerator on rat tissue O6-methylguanine (O6-meG) methyltransferase (MT) activity has been assessed using an assay which measures the transfer of 3H-radioactivity from 3H-methylated substrate DNA to protein. The maximal effect occurred 2 days after a 1 krad dose, at which time activity in liver extracts was increased approximately 5-fold in two different rat strains. Activity in lung and kidney was increased approximately 4- and 2-fold, respectively. Similar degrees of enhancement were found in these three tissues using an h.p.l.c. method for measuring MT activity. The increase in activity was reflected in an increased capacity to repair O6-meG produced in liver DNA by administration of [14C]dimethylnitrosamine (DMN): this effect was dose dependent, being detectable after 30 rads and maximal after 600 rads. Incorporation of labelled breakdown products of the DMN into adenine in DNA increased as the dose radiation increased suggesting an inhibition of DNA synthesis. The implications of these results for the mechanism of enhancing O6-meG repair are discussed.
Carcinogenesis 1985 Dec
PMID:O6-Methylguanine methyltransferase activity is increased in rat tissues by ionising radiation. 390 40

A diet that is deficient in methionine, choline, folic acid and vitamin B12 has been found to induce alterations rapidly in liver tRNA methylation in male Fischer rats. In vitro assays indicated that activity of N2-guanine tRNA methyltransferase II (NMG2) was increased to 150% of controls levels in 1 week and 300% of control levels after 2 weeks or longer on this diet. Incompletely methylated tRNA was isolated from livers of these same animals, indicating that there was impairment of methylation in vivo. The effects on liver tRNA methylation of this methyl-deficient diet were thus seen to mimic those of the liver carcinogen, ethionine, which also causes production of hypomethylated tRNA and increased activity of NMG2. The effect of the same diet on liver tRNA methyltransferase activity of C57BL/6J and C3H/HeJ inbred mice were also studied. Intake of the lipotrope-deficient diet induced elevation in activity of liver N2-guanine tRNA methyltransferase II activity in C57BL/6J mice, similar to that seen in rats. In contrast, the methyl-deficient diet had very little effect on the same enzyme activity in C3H/HeJ animals.
Carcinogenesis 1986 Mar
PMID:Altered tRNA methylation in rats and mice fed lipotrope-deficient diets. 394 30

The enzymatic repair of O4-methyldeoxythymidine (O4-MedT) by mammalian liver extracts was investigated in vitro using double-stranded poly[d(A-T) X d(A-T)] alkylated with N-[methyl-3H]-N-nitrosourea as a substrate. The removal of O4-MedT by monkey liver extracts was proportional to the protein concentration of the reaction mixture up to approximately 4 mg/ml, while kinetic analysis revealed the repair reaction reached a plateau by 2 h at 37 degrees C. The removal of O4-MedT could not be accounted for by contaminating nuclease activity, for greater than 90% of the 3-methyldeoxythymidine (3-MedT) was always recovered, whereas O4-MedT declined to as little as 25% of control values. A DNA-glycoslyase is not involved in the repair of O4-MedT, for O4-methylthymine, the free base, was not detected in supernatants from monkey liver reaction mixtures following incubation with substrate and precipitation of macromolecules with ethanol, even though analysis of nucleic acid digests of these assays revealed O4-MedT was lost from the substrate. The order of O4MedT repair activity in human, monkey, partially hepatectomized rat and methylguanine DNA-methyltransferase activity, with human and monkey most active, partially hepatectomized rat intermediate in activity and control rat least active. Our findings suggest the same, or a similarly regulated mammalian liver DNA-methyltransferase repairs O6-methylguanine and O4-MedT residues in DNA, yet the affinity of the enzyme(s) differs for these promutagenic adducts, as we estimate 30-50 O6-methylguanines would be repaired for every one O4-MedT repaired.
Carcinogenesis 1985 Feb
PMID:Repair of O4-methyldeoxythymidine residues in DNA by mammalian liver extracts. 397 96

The Burkitt's lymphoma cell line Raji has a Mex+ phenotype. It is more resistant to killing by alkylating agents than a sub line (Raji TK-) which is Mex-. A reduction in O6-methylguanine (O6MeG)-DNA methyltransferase can be brought about by growing Raji cells in the presence of free O6MeG. The depletion in enzyme activity is specific and reversible; removal of O6MeG from the medium results in the restoration of methyltransferase activity within 4 h. Raji cells, in which methyltransferase has been reduced by this treatment to below detectable levels, are not sensitised to killing by N-methyl-N'-nitro-N-nitrosoguanidine or the cross-linking nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-1-nitrosourea. This implies that adducts at the O6 atom of guanine in DNA are not potentially cytotoxic lesions. Secondly, it suggests that a defect other than the lack of methyltransferase is responsible for the sensitivity of Mex- cells to killing by alkylating agents.
Carcinogenesis 1985 May
PMID:The cytotoxic and mutagenic effects of alkylating agents on human lymphoid cells are caused by different DNA lesions. 400 64

We showed previously that resistance of a series of human fibroblast cell lines to the cytotoxic and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is highly correlated with their level of O6-methylguanine-DNA-methyltransferase (MT) activity. In the present study, MT activity in normal fibroblasts was decreased to between 40 and 20% of the constitutive level by 15 or 24 h exposure of the cells to exogenous O6-methylguanine (O6-MeG). MT-depleted and non-depleted populations were then challenged with various doses of MNNG and assayed for cytotoxicity and mutagenicity. At every dose the frequency of 6-thioguanine resistant cells induced by MNNG was higher in the MT-depleted populations than in the controls. Since the MT activity in these cells does not remove methyl from the O4 position of thymine, these results strongly support the hypothesis that O6-methylguanine is the principal mutagenic lesion induced by MNNG. Cells with decreased levels of MT were not significantly more sensitive to the cytotoxic effect of MNNG. If O6-methylguanine is a potentially cytotoxic lesion, this lack of increased sensitivity may reflect the fact that regeneration of MT protein occurred rapidly enough to remove these lesions before they resulted in cell death (i.e., inability to form a clone). Consistent with this explanation is the fact that 7 h after removal of the exogenous O6-MeG, the level of MT activity had regenerated to 51% of normal; by 18 h, it was 65% of normal.
Carcinogenesis 1985 Dec
PMID:Depletion of O6-methylguanine-DNA-methyltransferase in human fibroblasts increases the mutagenic response to N-methyl-N'-nitro-N-nitrosoguanidine. 406 56


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