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- W2102071927 endingPage "623" @default.
- W2102071927 startingPage "611" @default.
- W2102071927 abstract "Many tumors contain mutations that confer defects in the DNA-damage response and genome stability. DNA-damaging agents are powerful therapeutic tools that can differentially kill cells with an impaired DNA-damage response. The response to DNA damage is complex and composed of a network of coordinated pathways, often with a degree of redundancy. Tumor-specific somatic mutations in DNA-damage response genes could be exploited by inhibiting the function of a second gene product to increase the sensitivity of tumor cells to a sublethal concentration of a DNA-damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call synthetic cytotoxicity. We used the Saccharomyces cerevisiae nonessential gene-deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae ortholog of the mammalian tumor-suppressor gene, ATM. We found and validated 14 synthetic cytotoxic interactions that define at least five epistasis groups. One class of synthetic cytotoxic interaction was due to telomere defects. We also found that at least one synthetic cytotoxic interaction was conserved in Caenorhabditis elegans. We have demonstrated that synthetic cytotoxicity could be a useful strategy for expanding the sensitivity of certain tumors to DNA-damaging therapeutics." @default.
- W2102071927 created "2016-06-24" @default.
- W2102071927 creator A5028471378 @default.
- W2102071927 creator A5029318647 @default.
- W2102071927 creator A5081938339 @default.
- W2102071927 creator A5088317023 @default.
- W2102071927 date "2014-06-01" @default.
- W2102071927 modified "2023-09-28" @default.
- W2102071927 title "Synthetic Cytotoxicity: Digenic Interactions with TEL1/ATM Mutations Reveal Sensitivity to Low Doses of Camptothecin" @default.
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