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• W1025756728 abstract "AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA5733 Zalypsis® (PM00104) is a novel synthetic antineoplastic agent currently in Phase I clinical development. Zalypsis is related to the marine natural compounds Jorumycin and Renieramycin. It has strong antitumor activity in a wide variety of tumour lines in vitro and in vivo. Preliminary data suggests that the agent has DNA binding properties, induces cell cycle arrest and inhibits transcription. However, the precise mechanism of action of this agent remains mostly unknown. To provide some insight into the mode of action of Zalypsis in eukaryotic cells we have used the yeast Saccharomyces cerevisiae as a model system. We have screened the complete set of approximately 5,000 viable S. cerevisiae haploid deletion mutants to identify genes that, when deleted, confer sensitivity or resistance to Zalypsis. Using this method we identified approximately 350 mutants hypersensitive to the drug and about 90 mutants resistant to its activity. Mutants showing altered fitness in the presence of Zalypsis have been further analyzed, using concentrations above and below the ones employed in the screening. Therefore, we have generated a sensitivity / resistance profile specific for each mutant. Among the genes deleted in the 40 most sensitive strains we found those encoding components of the MRX complex, involved in sensing double strand breaks (DSB), as well as several members of the homologous recombination proteins of the Rad52 epistasis group, which are recruited to the sites of DNA damage specifically during S-phase and G2. In addition, some deletion mutants of the Swi/Snf complex, a chromatin remodeling complex conserved in humans, were also found to be extremely sensitive to the compound. It has been recently shown that inactivation of the Swi/Snf complexes results in inefficient DSB repair and increased DNA damage sensitivity as well as a large defect in H2AX phosphorylation (Park et al., EMBO J 25, 3986-3997, 2006). Altogether, these results reveal that the DNA damage repair machinery is essential to overcome Zalypsis induced DNA damage and suggest that this damage is mainly due to DSBs. In addition, we have also identified genes whose deletion confers resistance to Zalypsis. Among the 90 resistant mutants we found proteins involved in DNA metabolism and repair. The strain with a deletion of the gene encoding SUMO ligase Siz1 came up as one the most resistant mutants to Zalypsis. A role for this protein in the inhibition of homologous recombination at replication forks has been described recently (Watts, DNA Repair 5, 399-403, 2006), indicating again that the main lesions induced by Zalypsis are DSBs. The role of the genes encoding DNA interacting proteins in confering resistance to Zalypsis requires further investigation. Nevertheless our results indicate that these proteins are mediating the Zalypsis-induced cell death." @default.
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• W1025756728 date "2007-05-01" @default.
• W1025756728 modified "2023-10-02" @default.
• W1025756728 title "Genome-wide screen reveals antitumor Zalypsis® as a strong inducer of DNA double strand breaks" @default.
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