Li X, O'Neil NJ, Moshgabadi N, Hieter P

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 comprised of a network of coordinated pathways, often with ...

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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 sub-lethal concentration of a DNA damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call Synthetic Cytotoxicity. We used the Saccharomyces cerevisiae non-essential gene deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae orthologue 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 to expand the sensitivity of certain tumors to DNA damaging therapeutics.

Date: Mar. 20, 2014

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