Inhibitors of the RNA and DNA Dependent Polymerase Activities of RNA Tumour Viruses

Gurgo, Corrado; Ray, R.K.; Thiry, Lise; Green, Maurice

doi:10.1038/newbio229111a0

Cited by 92 publications

(53 citation statements)

References 22 publications

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“…He then showed that these nucleocapsids contained an endogenous DNA polymerase/reverse transcriptase activity that elongated nascent minus strands in a reaction that was resistant to actinomycin D. In contrast, elongation of plus strands (e.g., as in Fig. 1) was inhibited by actinomycin D. These observations fit nicely with earlier retrovirus studies showing that actinomycin D inhibited DNA-dependent but not RNA-dependent DNA synthesis (Gurgo et al 1971) and, along with other experiments, indicated that hepadnaviruses replicated via reverse transcription . Shortly thereafter, comparison of HBV and retrovirus nucleotide sequences revealed that HBV encodes the reverse transcriptase needed for its replication (Toh et al 1983).…”

Section: The Molecular Biology Of Hepadnaviruses As Deduced From Studsupporting

confidence: 79%

Animal Models and the Molecular Biology of Hepadnavirus Infection

Mason

2015

Cold Spring Harbor Perspectives in Medicine

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Australian antigen, the envelope protein of hepatitis B virus (HBV), was discovered in 1967 as a prevalent serum antigen in hepatitis B patients. Early electron microscopy (EM) studies showed that this antigen was present in 22-nm particles in patient sera, which were believed to be incomplete virus. Complete virus, much less abundant than the 22-nm particles, was finally visualized in 1970. HBV was soon found to infect chimpanzees, gorillas, orangutans, gibbon apes, and, more recently, tree shrews (Tupaia belangeri) and cynomolgus macaques (Macaca fascicularis). This restricted host range placed limits on the kinds of studies that might be performed to better understand the biology and molecular biology of HBV and to develop antiviral therapies to treat chronic infections. About 10 years after the discovery of HBV, this problem was bypassed with the discovery of viruses related to HBV in woodchucks, ground squirrels, and ducks. Although unlikely animal models, their use revealed the key steps in hepadnavirus replication and in the host response to infection, including the fact that the viral nuclear episome is the ultimate target for immune clearance of transient infections and antiviral therapy of chronic infections. Studies with these and other animal models have also suggested interesting clues into the link between chronic HBV infection and hepatocellular carcinoma.

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Section: The Molecular Biology Of Hepadnaviruses As Deduced From Studsupporting

confidence: 79%

Animal Models and the Molecular Biology of Hepadnavirus Infection

Mason

2015

Cold Spring Harbor Perspectives in Medicine

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“…2A and B. High concentrations of actinomycin D inhibit DNA-directed DNA synthesis, while N-deinethylrifampicin (at high concentrations) inhibits the endogenous DNA polymerase reaction of oncornaviruses (25). With high concentrations of actinomycin D, the endogenous DNA polymerase reaction of the lymphocyte "pellet" was inhibited by more than 85% (Fig.…”

Section: C2s0o4 Equilibrium Density-gradient Centrifugation Ofmentioning

confidence: 99%

“…2B) phase of the endogenous polymerase reaction of RNA tumor viruses (26). At concentrations of N-demethylrifampicin sufficient to inhibit crude preparations of RNA-directed DNA polymerase (25,27) or RNA-dependent reactions catalyzed by a DNA polymerase from leukemic cells (5), there was no inhibition of the endogenous, RNase-sensitive DNA synthesis of the "pellet" fraction of normal lymphocytes ( Fig. 2A).…”

Section: C2s0o4 Equilibrium Density-gradient Centrifugation Ofmentioning

confidence: 99%

Stimulated Normal Human Lymphocytes Contain a Ribonuclease-Sensitive DNA Polymerase Distinct from Viral RNA-Directed DNA Polymerase

Bobrow

Smith

Reitz

et al. 1972

Proc. Natl. Acad. Sci. U.S.A.

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Ribonuclease-sensitive DNA synthesis is demonstrated in a cytoplasmic particulate fraction of normal human blood lymphocytes stimulated with phytohemagglutinin, but not in unstimulated lymphocytes.DNA polymerase purified from this fraction does not transcribe the heteropolymeric regions of 70S RNA from RNA tumor viruses, thus distinguishing this enzyme from the RNA-directed DNA polymerase (reverse transcriptase) found in oncogenic RNA viruses and human leukemic cells.After the discovery of RNA-directed DNA polymerase (reverse transcriptase) in RNA tumor viruses (1-3), we undertook a search in both normal and neoplastic cells for this or a similar enzyme (4-6). Temin and others have suggested that RNA-instructed DNA synthesis may play a role in normal cellular differentiation, gene amplification, and in the secondary immune response (3, 5-9). The possible location of RNAdirected DNA polymerase in the cytoplasm of cells as either a viral or subviral particle, associated with an RNA template/primer, prompted a search for RNase-sensitive DNA synthesis directed by endogenous template/primers in highspeed, partially-purified "pellet" fractions from cytoplasms of mammalian cells (10, 11). Coffin and Temin (10) described such an endogenous RNase-sensitive DNA polymerase reaction in the high-speed cytoplasmic "pellet" of both virusinfected and uninfected rat tissue-culture cells. Ackermann et al. (11) described a similar reaction in a continuous cell line established from leukocytes of a patient with leukemia, but this cell line was thought to contain type-C viruses. Recently, RNase-sensitive DNA synthesis has been found in cytoplasmic fractions of fresh cells, including normal chick-embryo cells (12) and human leukemic blood leukocytes (13,14).Recently, reports have appeared showing that RNA may be a primer for DNA-directed DNA synthesis in bacterial (15, 16) and mammalian (17, 18) systems. Therefore, sensitivity of DNA synthesis to RNase in a complex system such as these cytoplasmic "pellets" (10-14) could be due to RNAprimed in contrast to RNA-directed DNA synthesis. One way to distinguish between a template and a primer role for RNA is to purify the DNA polymerase(s) from these "pellets" Abbreviation: PHA, phytohemagglutinin.

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“…An extensive discussion ensued about the distribution of this enzyme (particularly in virions and in cells from a variety of tumors) and the inhibition of the enzyme by some of the rifamycin derivatives (7)(8)(9)(10).…”

mentioning

confidence: 99%

Effect of Rifampicin and Two of Its Derivatives on Cells Infected With Moloney Sarcoma Virus

Calvin

Joss

Hackett

et al. 1971

Proc. Natl. Acad. Sci. U.S.A.

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It is shown that rifampicin, and especially the related antibiotic 2',6'-dimethyl-N(4')-benzyl-N(4')-[desmethylirifampicin (DMB-rifampicin) can inhibit focus formation by Moloney sarcoma virus on BALB/3T3 tissue cultures. At 10 ug/ml DMB-rifampicin totally inhibits focus formation while reducing virus replication by at least a factor of fifty and cell proliferation by only a factor of three. These observations, taken together with those of others, suggest a role for an RNA-dependent DNA polymerase and the gene for its synthesis both in normal cell processes and in the transformation process.

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Inhibitors of the RNA and DNA Dependent Polymerase Activities of RNA Tumour Viruses

Cited by 92 publications

References 22 publications

Animal Models and the Molecular Biology of Hepadnavirus Infection

Animal Models and the Molecular Biology of Hepadnavirus Infection

Stimulated Normal Human Lymphocytes Contain a Ribonuclease-Sensitive DNA Polymerase Distinct from Viral RNA-Directed DNA Polymerase

Effect of Rifampicin and Two of Its Derivatives on Cells Infected With Moloney Sarcoma Virus

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