This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Herrero, A. B. Articles by Moreno, S. Search for Related Content PubMed PubMed Citation Articles by Herrero, A. B. Articles by Moreno, S.

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

¹ Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca and ² Departamento de Farmacología, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

Requests for reprints: Sergio Moreno, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain. Phone: 34-92329-4810; Fax: 34-92329-4795; E-mail: smo{at}usal.es.

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/DNA-trabectedin ternary complex, stabilized by Arg961, results in cell death. (Cancer Res 2006; 66(16): 8155-62)

This article has been cited by other articles:

				J. A. Casado, P. Rio, E. Marco, V. Garcia-Hernandez, A. Domingo, L. Perez, J. C. Tercero, J. J. Vaquero, B. Albella, F. Gago, et al. Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin Mol. Cancer Ther., May 1, 2008; 7(5): 1309 - 1318. [Abstract] [Full Text] [PDF]

				Y. Pommier DNA Repair Modulators as Anticancer Agents ASCO Educational Book, January 1, 2008; 2008(1): 128 - 133. [Abstract] [Full Text] [PDF]

				D. G. Soares, A. E. Escargueil, V. Poindessous, A. Sarasin, A. de Gramont, D. Bonatto, J. A. P. Henriques, and A. K. Larsen From the Cover: Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743 PNAS, August 7, 2007; 104(32): 13062 - 13067. [Abstract] [Full Text] [PDF]