Low cytotoxicity of ecteinascidin 743 in yeast lacking the major endonucleolytic enzymes of base and nucleotide excision repair pathways

Soares, Daniele G.; Poletto, Nadine Paese; Bonatto, Diego; Salvador, Mirian; Schwartsmann, Gilberto; Henriques, João Antônio Pêgas

doi:10.1016/j.bcp.2005.04.013

Cited by 24 publications

(19 citation statements)

References 52 publications

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“…The formation of a putative Rad13/DNA-trabectedin cytotoxic ternary complex is consistent with earlier proposals that a protein/ DNA-trabectedin intermediate in the NER processing of trabectedin-DNA adducts could be trapped and give rise to the formation of cytotoxic complexes (17,38). DNA repair inhibition, rather than excision of the lesion, due to direct immobilization of NER factors by another type of adduct, has also been reported (39).…”

Section: Discussionsupporting

confidence: 90%

“…This delay was specifically abolished in a cds1D strain but not in a chk1D strain (Fig. 2C), corroborating the idea that trabectedin produces lesions in the DNA (9,17), and showing that it elicits DNA damage response in both S and G 2 phases.…”

Section: Resultssupporting

confidence: 81%

“…3C). The decreased sensitivity of this particular NER mutant to trabectedin has also been reported in mammalian cells (9) and in Saccharomyces cerevisiae (17), and suggests that Rad13 (XPG) is somehow involved in generating the DNA damage signal elicited upon trabectedin treatment.…”

Section: Resultssupporting

confidence: 58%

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Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

et al. 2006

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Trabectedin (Yondelis) is a potent antitumor drug that has the unique characteristic of killing cells by poisoning the DNA nucleotide excision repair (NER) machinery. The basis for the NER-dependent toxicity has not yet been elucidated but it has been proposed as the major determinant for the drug's cytotoxicity. To study the in vivo mode of action of trabectedin and to explore the role of NER in its cytotoxicity, we used the fission yeast Schizosaccharomyces pombe as a model system. Treatment of S. pombe wild-type cells with trabectedin led to cell cycle delay and activation of the DNA damage checkpoint, indicating that the drug causes DNA damage in vivo. DNA damage induced by the drug is mostly caused by the NER protein, Rad13 (the fission yeast orthologue to human XPG), and is mainly repaired by homologous recombination. By constructing different rad13 mutants, we show that the DNA damage induced by trabectedin depends on a 46-amino acid region of Rad13 that is homologous to a DNA-binding region of human nuclease FEN-1. More specifically, an arginine residue in Rad13 (Arg961), conserved in FEN1 (Arg314), was found to be crucial for the drug's cytotoxicity. These results lead us to propose a model for the action of trabectedin in eukaryotic cells in which the formation of a Rad13/DNAtrabectedin ternary complex, stabilized by Arg961, results in cell death. (Cancer Res 2006; 66(16): 8155-62)

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Section: Discussionsupporting

confidence: 90%

Section: Resultssupporting

confidence: 81%

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Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

et al. 2006

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“…Mammalian cells deficient in NER proteins such as the XPD and XPB helicases, and the XPG and ERCC1/XPF endonucleases showed 2-to 8-fold increased resistance to ET-743 in comparison with repair-proficient WT cells (1)(2)(3). Increased resistance to ET-743 was also reported for yeast mutants lacking the APN1 endonuclease, which particularly is involved in base excision repair (20). The unusual effect of these repair proteins on the cytotoxicity of ET-743 has been explained by the stabilization of repair complexes by the ET adducts (1)(2)(3)(4)21).…”

mentioning

confidence: 71%

“…Mismatch repair status had no detectable influence on the sensitivity to ET-743 (2, 6) whereas loss of the DNA-dependent kinase (DNA-PK) was reported to sensitize cells to ET-743 (2). Conflicting data have been reported for proteins involved in homologous recombination (HR) repair, because loss of repair function was associated with increased resistance to ET-743 in Saccharomyces cerevisiae (20) but increased sensitivity in Schizosaccharomyces pombe (21).…”

mentioning

confidence: 99%

Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743

Soares

Escargueil

Poindessous

et al. 2007

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

Self Cite

144

111

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Adducts induced by the antitumor alkylator ecteinascidin 743 (ET-743, Yondelis, trabectedin) represent a unique challenge to the DNA repair machinery because no pathway examined to date is able to remove the ET adducts, whereas cells deficient in nucleotide excision repair show increased resistance. We here describe the processing of the initial ET adducts into cytotoxic lesions and characterize the influence of cellular repair pathways on this process. Our findings show that exposure of proliferating mammalian cells to pharmacologically relevant concentrations of ET-743 is accompanied by rapid formation of DNA double-strand breaks (DSBs), as shown by the neutral comet assay and induction of focalized phosphorylated H2AX. The ET adducts are stable and can be converted into DSBs hours after the drug has been removed. Loss of homologous recombination repair has no influence on the initial levels of DSBs but is associated with the persistence of unrepaired DSBs after ET-743 is removed, resulting in extensive chromosomal abnormalities and pronounced sensitivity to the drug. In comparison, loss of nonhomologous end-joining had only modest effect on the sensitivity. The identification of DSB formation as a key step in the processing of ET-743 lesions represents a novel mechanism of action for the drug that is in agreement with its unusual potency. Because loss of repair proteins is common in human tumors, expression levels of selected repair factors may be useful in identifying patients particularly likely to benefit, or not, from treatment with ET-743.cancer therapy ͉ natural products ͉ lesion processing ͉ DNA repair ͉ response prediction

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Adiponectin, bile acids, and burnt-out nonalcoholic steatohepatitis: New light on an old paradox

Claudel

Trauner

2013

Hepatology

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Low cytotoxicity of ecteinascidin 743 in yeast lacking the major endonucleolytic enzymes of base and nucleotide excision repair pathways

Cited by 24 publications

References 52 publications

Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743

Adiponectin, bile acids, and burnt-out nonalcoholic steatohepatitis: New light on an old paradox

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