Cytotoxic and mutagenic effects of neocarzinostatin in wild-type and repair-deficient yeasts

Mousstacchi, E.; Favaudon, Vincent

doi:10.1016/0165-7992(82)90125-7

Cited by 25 publications

(6 citation statements)

References 27 publications

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“…Yeast grown in YPD at 30°C and exposed to NCS at a concentration of 50 g͞ml showed little evidence of growth inhibition relative to nontreated controls over the 4-h course of our experiments, consistent with the prior observations of Mousstacchi and Favaudon (23). NCS-treated yeast cells were enlarged relative to untreated controls after 12 h, a phenotype equated with aging (32).…”

Section: Resultssupporting

confidence: 80%

“…HeLa cells treated with NCS (Ϸ20 nM) show delayed entry into and prolonged progression through S phase and do not undergo the G 2 -M transition (22). By contrast, the growth of yeast (23), fungi (24), and Gram-negative bacteria (21) seems to be essentially unaffected, even in the presence of millimolar concentrations of NCS. The basis of this resistance is not known.…”

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confidence: 99%

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Gene transcription analysis of Saccharomyces cerevisiae exposed to neocarzinostatin protein– chromophore complex reveals evidence of DNA damage, a potential mechanism of resistance, and consequences of prolonged exposure

Schaus

Cavalieri

Myers

2001

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

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Section: Resultssupporting

confidence: 80%

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confidence: 99%

Gene transcription analysis of Saccharomyces cerevisiae exposed to neocarzinostatin protein– chromophore complex reveals evidence of DNA damage, a potential mechanism of resistance, and consequences of prolonged exposure

Schaus

Cavalieri

Myers

2001

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

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“…We found that B-CLL subsets that were resistant or sensitive to irradiation-induced apoptosis were also resistant or sensitive to apoptosis induced by NCS and the topoisomerase II inhibitor VP-16. NHEJ is the predominant pathway for the repair of both NCS-and topoisomerase II-mediated DNA damage: wild-type and repair-deficient yeasts and LIG4 Ϫ/Ϫ and Ku70 Ϫ/Ϫ cells, which are defective in NHEJ, are extremely sensitive to NCS 42,43 and to both We found that okadaic acid, an inhibitor of protein phosphatases 1 and 2A, induced apoptosis in both resistant and sensitive B-CLL samples, indicating the existence of a functional executive cell death pathway in resistant cells. Okadaic acid induces apoptosis in many cell types including B-CLL cells.…”

Section: Discussionmentioning

confidence: 99%

Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway

Deriano¹

2005

Blood

108

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Nonhomologous end-joining (NHEJ) DNA factors maintain genomic stability through their DNA double-strand break (DSB) repair and telomere-associated activities. Unrepaired or misrepaired DSBs can lead to apoptotic death or chromosomal damage. The B cells of some B-chronic lymphocytic leukemia (B-CLL) patients are resistant to radiation-induced apoptosis in vitro. We show here that the novel DNA-dependent protein kinase (DNA-PK) inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), and the phosphatidylinositol 3 (PI-3) kinase inhibitor, wortmannin, restored sensitivity to DNA damage-induced apoptosis of otherwise resistant cells. These resistant malignant B cells also escaped DSB-induced apoptosis following exposure to etoposide or neocarzinostatin. We found that at 15 minutes after irradiation, the levels of NHEJ (as measured by an in vitro DSB end-ligation assay) and DNA-PK catalytic subunit (DNA-PKcs) activity were, respectively, 2-fold and 4-fold higher in radioresistant than in radio- IntroductionMammalian cells respond to a variety of genotoxic stresses, including exposure to ionizing radiation and topoisomerase inhibitors, and endogenous reactive oxygen species, via 2 mechanisms for maintaining genome integrity: DNA repair and apoptosis. Inaccurate repair or a lack of repair of double-strand breaks (DSBs) can lead to apoptosis 1 or to mutations or large-scale genomic instability through the generation of nonlethal chromosomal aberrations. 2 DSBs are repaired by homologous recombination (HR) and by nonhomologous end-joining (NHEJ). NHEJ is the predominant mechanism in higher eukaryotes, whereas single-celled organisms (such as yeast) rely more heavily on HR. DNA-dependent protein kinase (DNA-PK) is a key component of the NHEJ pathway. 3 DNA-PK is a nuclear serine/threonine protein kinase, comprising a 460-kDa catalytic subunit, DNA-PKcs, and a DNA-binding subunit, the Ku autoantigen (a Ku70 and Ku80 protein dimer). The Ku70/Ku80 heterodimer binds the free DNA ends generated by DSBs and recruits the catalytic subunit of the complex. [4][5][6] In vitro, this active DNA-PK complex can phosphorylate many DNA-bound proteins including protein 53 (p53), Ku, X-ray cross-complementing group 4 (XRCC4), and DNA-PKcs 3,7,8 and can bind to XRCC4 and ligase IV, which join together the ends of the broken DNA strands. [8][9][10] Little is known about the role of the NHEJ repair pathway in apoptosis. Studies suggesting that DNA-PK plays a role in apoptosis remain controversial and principally relate to the interaction of this protein with p53. 11 The results from some studies indicate that DNA-PK activates and phosphorylates p53 12,13 and murine double mutant 2 (MDM2) 14 after DNA damage. However, other groups reported that DNA-PKcs-defective mice and DNAPKcs-defective cell lines display normal p53-mediated apoptosis responses. 15,16 DNA-PK activity has been implicated in resistance to nitrogen mustard therapy in leukemia cells, 17,18 but further studies are necessary to understand how these cells escape apoptosis aft...

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“…5) breaks. These include X rays (15,35), neocarzinostatin (28), and phleomycin (24). Regarding the excision-defective mutants studied, growth kinetic parameters of rad2-6 and rad3-eS showed minor modifications upon BLM treatment.…”

Section: Discussionmentioning

confidence: 99%

Effects of bleomycin on growth kinetics and survival of Saccharomyces cerevisiae: a model of repair pathways

1992

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In order to analyze the roles of some repair genes in the processing of bleomycin-induced DNA damage and, especially, the interrelationships among the involved repair pathways, we investigated the potentially lethal effect of bleomycin on radiosensitive mutants of Saccharomyces cerevisiae defective in recombination, excision, and R4D6-dependent DNA repair. Using single, double, and triple rad mutants, we analyzed growth kinetics and survival curves as a function of bleomycin concentration. Our results indicate that genes belonging to the three epistasis groups interact in the repair of bleomycin-induced DNA damage to different degrees depending on the concentration of bleomycin. The most important mechanisms involved are recombination and postreplication repair. The initial action of a potentially inducible excision repair gene could provide intermediate substrates for the R4D6-and RAD52-dependent repair processes. Interaction between R4D6 and RADS2 genes was epistatic for low bleomycin concentrations. RA1D3 and RAD52 genes act independently in processing DNA damage induced by high concentrations of bleomycin. The synergistic interaction observed at high concentrations in the triple mutant rad2-6 rad6-1 rad52-1 indicates partial independence of the involved repair pathways, with possible common substrates. On the basis of the present results, we propose a heuristic model of bleomycin-induced DNA damage repair.Bleomycin (BLM) is a radiomimetic glycopeptide antibiotic used extensively in tumor therapy (32,48). This drug binds to DNA and through a free-radical-based mechanism produces DNA base loss and single-and double-strand breaks (43,44). In different lines of eukaryotic cells, BLM produces inhibition of DNA synthesis (10) as well as cell cycle G2 delay (19,38). With phages, bacteria, and yeast cells, it was demonstrated that this drug is recombinogenic and mutagenic (11,23,39,42). Analysis of BLM-induced mutagenesis in repackaged lambda phage suggests SOS repair dependence (33).BLM-induced DNA damage in prokaryotic and eukaryotic cells is partially reparable (3,22,27,40). For human fibroblasts, a long-patch mode of excision repair of BLM-induced damage was recently described (4, 5). Using haploid and diploid radiosensitive strains of Saccharomyces cerevisiae, Moore (22) showed that all rad single mutants sensitive to BLM tested, with the exception of rad1S, are sensitive to X rays. Likewise, BLM-sensitive (blm) mutants exhibit crosssensitivity to ionizing radiation and hydrogen peroxide (26). These results suggest that some aspects of the repair of BLM and ionizing radiation DNA damage in yeast cells may be similar. Furthermore, DNA ligase (the product of the CDC9 gene) is required in the overall process of restoring full-size DNA molecules from DNA fragments produced by BLM (24, 25).We have recently shown that BLM induces at least one error-prone type of repair in S. cerevisiae and that the PS04 (XS9) gene acts as a mutation-triggering factor (39). Furthermore, the combination of UV light and BLM produces di...

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Cytotoxic and mutagenic effects of neocarzinostatin in wild-type and repair-deficient yeasts

Cited by 25 publications

References 27 publications

Gene transcription analysis of Saccharomyces cerevisiae exposed to neocarzinostatin protein– chromophore complex reveals evidence of DNA damage, a potential mechanism of resistance, and consequences of prolonged exposure

Gene transcription analysis of Saccharomyces cerevisiae exposed to neocarzinostatin protein– chromophore complex reveals evidence of DNA damage, a potential mechanism of resistance, and consequences of prolonged exposure

Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway

Effects of bleomycin on growth kinetics and survival of Saccharomyces cerevisiae: a model of repair pathways

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