DNA alkylation tolerance is a major concern in cancer chemotherapy. It has been suggested that mutations in DNA mismatch repair genes may result in alkylation tolerance. This alkylation tolerant phenotype is often manifested in cells lacking an O(6)-methylguanine DNA methyltransferase (MTase) activity. However, deletion of each mismatch repair gene in the MTase mutant of a model eukaryotic yeast does not result in alkylation tolerance. We previously isolated an alkylation tolerant mutant and mapped the mutation to MSH5. Here we present evidence that a single point mutation that results in a Y823H amino acid substitution, but not deletion, of the MSH5 gene is responsible for tolerance to killing by DNA alkylating agents. We also find that other preexisting amino acid variations may also enhance alkylation tolerance in the above mutation background. Since MSH5 encodes a protein homologous to DNA mismatch recognition proteins, mismatch repair genes are frequently mutated in cancers cells and, like mismatch repair genes, MSH5 is highly conserved from yeast to human, this observation suggests novel mechanisms of chemotherapeutic drug resistance that may occur in certain human cancer patients.
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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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