Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of a new nitrosourea (TCNU) based on the endogenous amino acid taurine was assessed in three human lung cancer xenografts growing in immunodeficient mice. Moderate activity (specific growth delays of 0.63 and 1.13 compared with controls) was seen in two non-small cell tumours after a single oral administration of 20 mg-1kg. This dose was curative in a small cell xenograft. By using high performance liquid chromatography it was possible to detect parent drug in the tumours as well as the plasma and tissues after oral administration of TCNU. Drug sensitivity was correlated inversely with the amount of the DNA repair enzyme 0(6)-methylguanine-DNA methyltransferase assayed from extracts of the tumour cells but not with the levels of parent drug within the tumour. This compound appears to have unique pharmacokinetic properties compared with other chloroethylnitrosoureas.
Br J Cancer 1988 Apr
PMID:Activity of a new nitrosourea (TCNU) in human lung cancer xenografts. 339 Mar 69

The induction of differentiation in several tumor lines serves as a basis for a new approach to cancer treatment. In vitro studies in the mouse erythroleukemia (MEL) cell system have identified about 300 agents capable of inducing differentiation by mechanisms that remain to be elucidated. The design of differentiation therapy will depend on the specific tumor cell type, an effective time course, and the synergistic interaction among combinations of two or more inducers. The induction of differentiation may be followed by terminal cell division (TCD) or programmed cell death in several tumor cell systems. This mechanism for the destruction of tumor cells is one goal of differentiation therapy and differs from nonspecific cytotoxic therapy. To evaluate the effect of differentiation therapy, a clear distinction must be made between nonspecific cytotoxicity and the programmed TCD of induced cytodifferentiation. One possible parameter for assessing the commitment to TCD in the MEL cell system is a selective decrease in DNA ligase activity, which does not appear to occur following treatment with nonspecific cytotoxic agents. These biological and biochemical parameters should be helpful in designing agents capable of inducing TCD in vivo.
Cancer Detect Prev 1986
PMID:Basic principles for utilizing combination differentiation agents. 352 18

Since interferon inducible 2',5'-oligoadenylate (2,5An) synthetase activity is present in a wide variety of cells and is affected by various hormonal conditions, primary human mammary tumor extracts were examined for the constitutive presence of this enzyme and its possible relationship with the various hormonal receptor levels in these tissues. Further, since 2,5An synthetase has been implicated as a possible factor controlling cell replication, we assayed DNA polymerases in these same tumor extracts to determine any correlation between 2,5An synthetase activity and growth potential. A survey of the soluble extracts from 24 different surgically removed human mammary tumor specimens for 2,5An synthetase activity indicated that this enzyme was indeed present in all extracts but in widely varying amounts of activity (31-2,666 nmol adenosine 5'-phosphate incorporated/mg protein). The 2,5An synthesized in the enzymic reactions ranged in size from di- to hexamers, with trimers being the abundant 2,5An in the majority of tumors. A comparison of the assay results for estrogen and progestin receptors with 2,5An synthesis indicated that high 2,5An synthetase activity was found in both estrogen or progestin positive and negative tumors. Thus, 2,5An synthetase activity was unrelated (r = 0.329 and 0.077, respectively, for estrogen and progestin receptors) to the hormonal receptor content of these tumors. A similar comparison was made between 2,5An synthesis and assay results for the activities of DNA polymerase alpha, regarded as the principal DNA replicating enzyme, and DNA polymerase beta, regarded as the DNA repair enzyme. Although the activity of the polymerases were also quite varied, the majority of tumor extracts demonstrated higher alpha polymerase activity with no parallel difference between the alpha and beta enzymes. There was, however, a weak correlation (r = 0.751) between 2,5An synthetase activity and DNA polymerase alpha activity among the tumors examined. Less of a correlation existed with DNA polymerase beta activity (r = 0.600). These results suggested that the potential of the tumors to synthesize 2,5An was unrelated to their hormonal responsiveness and only weakly related to their growth potential reflected by DNA polymerase alpha activity.
Cancer Res 1986 Dec
PMID:2',5'-oligoadenylate synthetase activity in human mammary tumors and its potential correlation with tumor growth or hormonal responsiveness. 377 41

The biosynthesis of the human DNA repair enzyme uracil-DNA glycosylase has been characterized by the reaction of in vitro- and in vivo-produced protein with an anti-human placental uracil-DNA glycosylase monoclonal antibody. In vitro synthesis of the DNA repair enzyme was examined after the translation of human placental polyadenylated [poly(A)+] RNA by immunoprecipitation of the [35S]methionine-labeled translation products. As defined by sucrose density analysis, immunoprecipitable in vitro products were translated from 16S poly(A)+ RNA and 11S poly(A)+ RNA. While the products of the 11S poly(A)+ RNA were smaller than purified uracil-DNA glycosylase, the product of the 16 S poly(A)+ RNA had a molecular weight of 37,000, identical to the size previously observed for purified human placental uracil-DNA glycosylase. Immunoblot analysis of human placental cell extracts and of normal human fibroblast cell extracts demonstrated the recognition of one Mr 37,000 protein. Immunoprecipitation of [35S]methionine-labeled normal human cell extracts with the anti-glycosylase monoclonal antibody specifically detected only the Mr 37,000 uracil-DNA glycosylase protein. Pulse-chase analysis demonstrated that the 35S radioactivity in the Mr 37,000 uracil-DNA glycosylase decreased over a 5-h interval. These results show that immunoreactive human uracil-DNA glycosylase protein was synthesized at its enzymatically active molecular weight of 37,000 as the primary translation product of a 16S polyadenylated messenger RNA.
Cancer Res 1987 Jan 01
PMID:Biosynthesis of the human base excision repair enzyme uracil-DNA glycosylase. 379 Nov 99

Certain rare human diseases with autosomal recessive mode of inheritance are associated with a greatly increased cancer frequency which may reflect specific defects in DNA repair or replication. These disorders include xeroderma pigmentosum, ataxia-telangiectasia, Fanconi's anaemia and Bloom's syndrome. Cells from individuals with Bloom's syndrome usually grow slowly in culture and exhibit increased chromosomal breakage and rearrangement, an elevated frequency of sister chromatid exchanges, retarded rates of progression of DNA replication forks, delayed conversion of replication intermediates to high-molecular-weight DNA, and slightly increased sensitivity to DNA-damaging agents. Several of these features are also characteristic of Escherichia coli and yeast mutants with a defective DNA ligase. In this investigation we show that one of the two DNA ligases of human cells, ligase I, is defective in a representative lymphoid cell line of Bloom's syndrome origin.
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PMID:DNA ligase I deficiency in Bloom's syndrome. 380 31

Cells from patients with Bloom's syndrome, a rare disease associated with increased cancer frequency, exhibit cytological abnormalities. These include increased numbers of homologous chromatid interchange figures and sister-chromatid exchanges, together with abnormally slow replicon-fork progression and retarded rate of DNA-chain maturation, and suggest that the primary defect in this recessive disorder affects S-phase DNA replication. DNA ligases and DNA polymerases have long been prime candidates for abnormality in Bloom's syndrome, but various studies of DNA polymerases in Bloom's syndrome cells have disclosed no abnormalities. Evidence is presented here, as in the accompanying paper from a different laboratory, for the existence in Bloom's syndrome of an abnormality of the DNA ligase involved in semi-conservative DNA replication.
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PMID:Altered DNA ligase I activity in Bloom's syndrome cells. 380 32

Human DNA ligase was purified from both normal and leukemic peripheral lymphocytes and normal thymocytes. The activity of the purified enzymes was assayed in the presence of several widely used antileukemic drugs. Melphalan and prednisone at 5 mM had no effect. Carmustine, chlorambucil, and cyclophosphamide were more effective at inhibiting the enzyme from leukemic cells, whereas Adriamycin and vinblastine and their derivatives were stronger inhibitors of the enzyme from normal cells. Vincristine and etoposide inhibited DNA ligase from thymocytes and normal lymphocytes with a low Ki but were totally ineffective on the enzyme from leukemic cells. The three classes of intercalating anthracyclines, Vicia alkaloids, and podophyllotoxin derivatives, were the only drugs found to markedly inhibit DNA ligases from normal cells. Less substituted molecules of the Vicia alkaloids and podophyllotoxin classes were the more active inhibitors, whereas in the intercalating anthracycline group, it was the more substituted compounds. The clinical consequences of these observations are discussed with respect to the role of DNA ligase in DNA replication and repair.
Cancer Res 1985 May
PMID:Inhibition of DNA ligase from human thymocytes and normal or leukemic lymphocytes by antileukemic drugs. 398 68

A rapid method for the extraction and purification of DNA from human leukocytes was developed. Crude nucleic acids were obtained by sodium dodecylsulfate (SDS) lysis and potassium acetate precipitation of other cellular material, and the DNA was purified by ribonuclease digestion, diethylaminoethyl (DEAE) cellulose chromatography and ethanol precipitation. DNA obtained by this method is biologically active as reflected by its ability to act as substrate for various nucleases and T4 DNA ligase. The yield was sufficiently high that DNA from less than 1 ml of blood could be used for a number of reactions.
Cancer Lett 1985 Apr
PMID:A rapid method for the extraction and purification of DNA from human leukocytes. 399 5

DNA repair proficiency in cells is expressed by various enzymes which can recognize damaged sites arising from exogenous agents or endogenous conditions. Either a damaged base is recognized by DNA glycosylases, partially removed by hemi-DNA glycosylases acting on diadduct damage, or direct incision of the phosphodiester bond near the damaged site. Incision at those apurinic or apyrimidinic sites arising from depurination-depyrimidination or glycosylase reactions is effected by apurinic or apyrimidinic endonucleases. Excision of damaged sites is catalyzed by unique exonucleases followed by DNA polymerase catalyzed reinsertion of nucleotides. The integrity of the strands is restored by polynucleotide ligase when a juxtaposed nucleotide is properly reinserted.
Natl Cancer Inst Monogr 1981 Dec
PMID:Enzymatic mechanisms of DNA repair. 628 49

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


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