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Using Genetic Buffering Relationships Identified in Fission Yeast To Elucidate the Molecular Pathology of Tuberous Sclerosis

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The University of Western Ontario London, Ontario Canada

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Using the genetically tractable fission yeast as a model, we sought to exploit recentadvances in gene interaction biology to identify novel drug targets for use in the fightagainst tuberous sclerosis. Our ongoing study has identified two genes, fft3 a SMARCAD1family ATP-dependent DNA helicase and ypa1 protein phosphatase type 2A regulator asexcellent candidates for continued analysis. While deletion of either gene has littlephenotypic effect in normal cells, their loss in either tsc1 or tsc2 gene deletion mutantsprofoundly inhibits growth. Significantly, we show that a subset of tsc2 mutants bearingmutations orthologous to those found clinically also display synthetic lethal interactionswith fft3 and ypa1. Furthermore, we show that the loss of fft3 ATPase activity, through thecreation of an fft3-K418R mutant, is sufficient to confer a synthetic growth defect. Thesedata suggest that inhibition of either ypa1 or fft3 through targeting the ATPase domain mayrepresent an Achilles heel of cells defective in hamartin or tuberin function.

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Technical Report,01 Jul 2015,30 Jun 2016



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Approved For Public Release;

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