We have developed a system utilizing the yeast Saccharomyces cerevisiae to probe the mechanism of action of anti-topoisomerase II drugs. This system has enabled us to dissect the mechanism of action of these agents. By inducing the overexpression of yeast topoisomerase II or by reducing the level of activity using temperature-sensitive mutations in topoisomerase II, we have demonstrated that conversion of topoisomerase II to a cellular poison plays a critical role in cell killing. We have also constructed other mutations in the yeast TOP2 gene that are resistant to etoposide and amsacrine and determined the DNA sequences for several of the drug-resistant alleles. The mutations that confer drug resistance map to several regions of the TOP2 gene. A mutation of particular interest changes Ser741 to Trp. This mutation results in hypersensitivity to etoposide but does not alter sensitivity to other agents such as mAMSA. We suggest that this mutation defines a site on the TOP2 protein that is involved in drug:protein interactions.
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| Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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| Site | Modification | Modifier | Source | Reference |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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| Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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| Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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