Aphidicolin: A specific inhibitor of DNA polymerases in the cytosol of rat liver

Ohashi, Masataka; Taguchi, Takahiko; Ikegami, Susumu

doi:10.1016/0006-291x(78)90298-x

Cited by 144 publications

(36 citation statements)

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“…The multiplication of herpes virus, vaccinia virus and SV40 is also sensitive to aphidicolin (1,4,20). Recently it has been reported that DNA polymerase a from various sources is strongly inhibited by low concentrations of aphidicolin while DNA polymerase 0 and y are resistant to drua concentrations up to 10-3 M (2,3,4,5,17,20). The sensitivity of both cellular or SV40 DNA replication and DNA polymerase a supports the hypothesis that DNA polymerase a is required for papovavirus DNA synthesis and DNA synthesis in uninfected mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

Differential effect of aphidicolin on adenovirus DNA synthesis and cellular DNA synthesis

Kwant

Vliet

1980

Nucl Acids Res

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There is strong evidence for a participation of DNA polymerase y in the replication of adenovirus (Ad) DNA. To study a possible additional role of DNA polymerase a we measured the effect of aphidicolin on viral DNA replication.In intact cells, aphidicolin inhibits Ad DNA synthesis weakly. The drug concentration required for 50% inhibition of Ad DNA replication was 300-400 fold higher than for a similar effect on cellular DNA synthesis. Such a differential inhibition was also observed in AGMK cells doubly infected with SV40 and the simian adenovirus SA7. No evidence was found for modification of aphidicolin in infected cells or for a change in aphidicolin sensitivity of DNA polymerase a after infection.The extent of inhibition of purified DNA polymerase a was dependent upon the dCTP concentration. The same situation was observed when DNA synthesis was studied in isolated nuclei from uninfected cells. However, in nuclei from Ad infected cells no effect of dCTP on aphidicolin sensitivity was found. These results were taken as evidence that DNA polymerase a does not participate in the replication of adenovirus DNA.

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Section: Introductionmentioning

confidence: 99%

Differential effect of aphidicolin on adenovirus DNA synthesis and cellular DNA synthesis

Kwant

Vliet

1980

Nucl Acids Res

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“…Aphidicolin also inhibits not only DNA replication in HeLa cells but UV-induced DNA repair in hydroxyurea-arabinosyl cytosine treated cells (5). Furthermore, aphidicolin is known to suppress selectively the activity of DNA polymerase a, which is assumed to be the replication enzyme in DNA synthesis (6), but not that of DNA polymerase (3 or r obtained from sea urchin blastulae (3) and rat liver cytosol (7).…”

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confidence: 99%

Aphidicolin: A specific inhibitor of DNA synthesis in synchronous mastocytoma P-815 cells.

Ichikawa¹,

Negishi²,

Tomita³

et al. 1980

Jpn.J.Pharmacol

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Abstract-Theinfluence of aphidicolin on cell multiplication and DNA synthesis was examined using synchronous mouse mastocytoma P-815 cells. Aphidicolin was cytotoxic specifically to the cells of the S phase of the cell cycle. This cytotoxicity was reversed by appropriately washing the drug-treated cells, but not by the addition of deoxyribonucleosides.Aphidicolin, a potent inhibitor of DNA synthesis, selectively inhibited the activity of partially purified DNA polymerase a from the nucleus and the cytosol of mastocytoma cells, but did not affect the activity of DNA polymerase (3 . Furthermore, aphidicolin had no effect on the synthesis of RNA and protein, and produced no changes in cell size at least for one generation.Aphidicolin, a tetracyclic diterpenoid antibiotic produced by the mold Cephalosporium aphidicola (1), has been reported to inhibit growth of herpes simplex virus both in rabbit eye and in tissue culture (2), DNA synthesis in cultured human embryonic lung cells (2), and mitotic cell division of sea urchin embryos (3, 4). Aphidicolin also inhibits not only DNA replication in HeLa cells but UV-induced DNA repair in hydroxyurea-arabinosyl cytosine treated cells (5). Furthermore, aphidicolin is known to suppress selectively the activity of DNA polymerase a, which is assumed to be the replication enzyme in DNA synthesis (6), but not that of DNA polymerase (3 or r obtained from sea urchin blastulae (3) and rat liver cytosol (7).Since these observations indicate that interference of aphidicolin with DNA synthesis is responsible for its cytocidal effect, we examined the effect of the drug on the cell division cycle using synchronous mammalian cells, mouse mastocytoma P-815 cells, in culture, and our results are reported herein. MATERIALS AND METHODSCell growth and viability test: Mouse mastocytoma P-815 cells (8) were provided by Dr. M. Potter, National Cancer Institute, NIH, Bethesda, Maryland, U.S.A., and main tained in suspension culture in Fischer-Sartorelli's medium supplemented with 5 % fetal calf serum at 37.5'C in a 5 % C02-containing humidified atmosphere. Stock cultures were diluted every 1 or 2 days with the fresh medium to maintain the exponential growth at the

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“…Aphidicolin inhibits cellular DNA synthesis but does not inhibit protein and RNA synthesis. Aphidicolin inhibits the activity of DNA polymerase a without affecting the activity of DNA polymerases (3 and r, 7,9) suggesting that DNA polymerase a is the enzyme responsible for cellular DNA replication. The unusual and remarkable activity of aphidicolin on cellular and enzymatic functions as revealed by these experiments prompted us to report on the preparation of HC_ and 3H-Iabelled aphidicolin in order to study further the mode of inhibitory action of S. IKEGAMI, K. OKANO and H. MURAGAKI…”

Section: S)mentioning

confidence: 99%

Synthesis of Radioactive Aphidicolin, a Potent Inhibitor of DNA Replication in Eukaryotic Cells

Ikegami

Okano

Muragaki

1979

Agricultural and Biological Chemistry

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Aphidicolin: A specific inhibitor of DNA polymerases in the cytosol of rat liver

Cited by 144 publications

References 3 publications

Differential effect of aphidicolin on adenovirus DNA synthesis and cellular DNA synthesis

Differential effect of aphidicolin on adenovirus DNA synthesis and cellular DNA synthesis

Aphidicolin: A specific inhibitor of DNA synthesis in synchronous mastocytoma P-815 cells.

Synthesis of Radioactive Aphidicolin, a Potent Inhibitor of DNA Replication in Eukaryotic Cells

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