Using genetic buffering relationships identified in fission yeast to reveal susceptibilities in cells lacking hamartin or tuberin function.

Tuberous sclerosis complex is an autosomal dominant disorder characterized by benign tumors arising from the abnormal activation of mTOR signaling in cells lacking TSC1 (hamartin) or TSC2 (tuberin) activity. To expand the genetic framework surrounding this group of growth regulators, we utilized the model eukaryote to uncover and characterize genes that buffer the phenotypic effects of mutations in the orthologous or loci. Our study identified two genes: (encoding a DNA helicase) and (encoding a peptidyle-prolyl cis/trans isomerase). While the deletion of or has little effect in wild-type fission yeast cells, their loss in or backgrounds results in severe growth inhibition. These data suggest that the inhibition of Ypa1p or Fft3p might represent an 'Achilles' heel' of cells defective in hamartin/tuberin function. Furthermore, we demonstrate that the interaction between / and can be rescued through treatment with the mTOR inhibitor, torin-1, and that cells are resistant to the glycolytic inhibitor, 2-deoxyglucose. This identifies as a novel upstream regulator of mTOR and suggests that the effects of loss, together with mTOR activation, combine to result in a cellular maladaptation in energy metabolism that is profoundly inhibitory to growth.