Role of poly(adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts

James, M. R.; Lehmann, Alan R.

doi:10.1021/bi00260a016

Cited by 143 publications

(30 citation statements)

References 32 publications

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“…Nate Acad ScL USA 81 (1984) 245 posed to radiation or chemicals at various doses were in the range of i0-4 to 10-2 foci per survivor and were higher in the hamster cells (Tables 1 and 2). BzA (1 mM) and 3ABzA (1 mM) had no influence alope but reduced transformation frequencies in both cell types for each damaging agent, with no significant effects on cell survival, unlike the increased toxicity seen in other cell types (18,19) (Tables 1 and 2). BzA and 3ABzA had essentially the same effect on transformation frequencies except for C3H lOT'/2 cells irradiated with x-rays (Table 1), in which BzA was more effective.…”

Section: Resultsmentioning

confidence: 92%

“…When cells are exposed to DNA-damaging agents, single-strand breaks are produced in the DNA. The frequency of breaks represents a dynamic balance between rates of direct and enzymatic strand breakage and rates of ligation (16)(17)(18)(19)(20). A representative example of strand break measurements in C3H lOT'/2 cells is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Poly(ADP-ribose) synthesis is transient after exposure of cells to ionizing radiation but long lasting after exposure to alkylating agents and UV light, corresponding to the period during which DNA breaks are detectable (16,18,19). Despite the large difference in poly(ADP-ribosyl)ation, transformation is suppressed after exposure to each kind of agent (Tables 1 and 2), suggesting that transformation frequency is not directly dependent on the total amount and duration of poly(ADP-ribosyl)ation but more likely is dependent on specific proteins that are ADP-ribosylated.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis.

Borek¹,

Morgan²,

Ong³

et al. 1984

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

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Malignant transformation in vitro of hamster embryo cells and mouse C3H lOT'/2 cells by x-rays, ultraviolet light, and chemical carcinogens was inhibited by benzamide and by 3-aminobenzamide at concentrations that are specific for inhibition of poly(ADP-ribose) formation. These compounds slow the ligation stage of repair of x-ray and alkylation damage but not of ultraviolet light damage. At high concentrations they also inhibited de novo synthesis of DNA purines and DNA methylation by S-adenosylmethionine. The suppression of transformation by the benzamides is in striking contrast to their reported effectiveness in enhancing sister chromatid exchange, mutagenesis, and killing in cells exposed to alkylating agents. Our results suggest that mechanisms regulating malignant transformation are different from those regulating DNA repair, sister chromatid exchange, and mutagenesis and may be associated with changes in gene regulation and expression caused by alterations in poly(ADP-ribosyl)ation.Malignant transformation of cells in vitro by radiation or chemical carcinogens is a reproducible quantitative system for studying the mechanisms of carcinogenesis (1-7). Although fixation of transformation and mutagenesis involves DNA metabolism and cell replication (2, 4-6), the numbers and kinds of genes involved are not known. Poly(ADP-ribose) is an important cellular regulatory molecule (8, 9) and its synthesis can be inhibited by 3-aminobenzamide (3ABzA) and benzamide (BzA). We therefore investigated the effects of these inhibitors on transformation by a variety of DNAdamaging agents with careful comparison to their effects on DNA repair and nucleotide precursor pathways over a range of concentrations. These agents, at concentrations below those at which side effects were evident, inhibited malignant transformation in vitro, in contrast to their reported enhancement of sister chromatid exchange (10-12) and mutagenesis (13) Mouse embryo fibroblast cells C3H 10T1/2 (clone 8), originally obtained from C. Heidelberger (University of Southern California, Los Angeles), were treated as described (3,7). Stock cultures were maintained at 370C, aerated with 5% CO2 in air, in Eagle's basal medium containing 10% heatinactivated fetal calf serum, penicillin (50 units/ml), and streptomycin (50 tkg/ml).At 24 hr after plating, cells were irradiated with a Siemens 300-kVp constant-potential generator with an additional filter of 0.2 mm of Cu at room temperature with 3 or 4 Gy of xrays at a dose rate of 0.322 Gy/min and incubated at 37°C in 5% C02/95% air with weekly changes of medium. After a 10-day incubation period for the hamster cells (1, 2) and 6 weeks for the lOT1/2 cells (2, 3, 7), cultures were fixed and stained with Giemsa stain. Assays for cell survival, cloning efficiency, and transformation were carried out as described previously for the hamster cells (1-4) and for the C3H 10T1/2 cells (2, 3, 7). For experiments with UV light, C3H 10T1/2 cells were exposed to 10-13 J/m2 (254 nm, dose rate of 0.15-1.3 J/m2_sec).For ex...

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis.

Borek¹,

Morgan²,

Ong³

et al. 1984

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

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“…A role for PARP-1 in the repair of DNA double-strand breaks (DSB) has also been suggested (14,15). However, PARP-1 À/À cells display normal DSB repair through nonhomologous end joining as well as homologous recombination (16), and it has been shown that PARP-1 is not involved in recovery from DSB induced by g-rays (17), etoposide (18), or neocarzinostatin (19); yet, post-transcriptional ADP-ribosylation of some repair proteins affects their DNA-binding ability and catalytic activity (6).…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis

Noël

Godon

Fernet

et al. 2006

Molecular Cancer Therapeutics

114

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“…It inhibits the repair of DNA damage induced by various alkylating agents or by yirradiation. Previous reports suggest that it is the ligation of DNA during the repair process that is impaired (14)(15)(16)(17). In agreement with this suggestion, it has recently been shown that alteration of chromatin structure by poly(ADP-ribose) synthetase influences the activity of the DNA ligases (18).…”

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confidence: 99%

Accumulation of 10-kilobase DNA replication intermediates in cells treated with 3-aminobenzamide.

Lönn¹,

Lönn²

1985

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

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During eukaryotic DNA synthesis there is formation of, in addition to Okazaki fragments, discrete 10-kilobase (kb) DNA replication intermediates. We have investigated the ligation of 10-kb DNA replication intermediates to high molecular weight DNA, using the drug 3-aminobenzamide, an inhibitor of poly(ADP-ribose) synthetase. In human melanoma cells treated with this inhibitor, there is an accumulation of 10-kb DNA. In contrast, in cells treated with aphidicolin, which inhibits DNA polymerase a, there is continued ligation of 10-kb DNA to high molecular weight DNA. Furthermore, using sequential treatment with aphidicolin and 3-aminobenzamide, one can observe the conversion of radiolabeled Okazaki fragments into 10-kb intermediates. The 10-kb DNA pieces are, however, not ligated to high molecular weight DNA in the presence of 3-aminobenzamide. Our results imply that functioning poly(ADP-ribose) synthetase is necessary for the ligation process.Eukaryotic DNA synthesis is very complex and there exist several steps in the synthetic pathway that are not understood (1). For example, we know very little about the steps in the maturation of primary DNA replication intermediates (Okazaki fragments) to high molecular weight DNA. Our inability to examine this process has been due in part to the large size of the eukaryotic genome, which has made it difficult to detect defined DNA replication intermediates that are larger than Okazaki fragments.We have examined the ligation of a large DNA replication intermediate. Using a novel procedure to lyse cells in dilute alkali, we have detected at least two discrete DNA replication intermediates, Okazaki fragments and 10-kilobase (kb) fragments (2-4). The formation of both the Okazaki fragments and 10-kb DNA replication intermediates is dependent on DNA polymerase a (3). However, the ligation of 10-kb DNA to high molecular weight DNA still occurs when DNA polymerase a is inhibited by aphidicolin.Poly(ADP-ribose) synthetase catalyzes the poly(ADP-ribosyl)ation of chromosomal proteins (5)(6)(7)(8). Histones, mainly histone H1, are the major acceptors. Much work has been performed in attempts to understand the biological significance of this secondary modification. It is known that the poly(ADP-ribosyl)ation of histones results in relaxation of polynucleosomes (9, 10) and that the activity of poly(ADPribose) synthetase is dependent on nicks in the DNA (5)(6)(7)(8)11). In cells synchronized with a G1 block, poly(ADP-ribosyl)ation exhibits a cell cycle-dependent oscillation with a maximum coinciding with S phase (12). This observation suggests connection between poly(ADP-ribose) synthetase and S-phase events, such as DNA synthesis.Poly(ADP-ribose) synthetase can be inhibited using the drug 3-aminobenzamide (13), which is a competitive inhibitor that appears to be highly specific. It inhibits the repair of DNA damage induced by various alkylating agents or by yirradiation. Previous reports suggest that it is the ligation of DNA during the repair process that is impaired (14-17). In...

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Role of poly(adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts

Cited by 143 publications

References 32 publications

Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis.

Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis.

Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis

Accumulation of 10-kilobase DNA replication intermediates in cells treated with 3-aminobenzamide.

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