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  Schizosaccharomyces pombe  to uncover and characterize genes that buffer the phenotypic effects of mutations in the orthologous  tsc1  or  tsc2  loci. Our study identified two genes:  fft3  (encoding a DNA helicase) and  ypa1  (encoding a peptidyle-prolyl cis/trans isomerase). While the deletion of  fft3  or  ypa1  has little effect in wild-type fission yeast cells, their loss in  tsc1Δ  or  tsc2Δ  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  tsc1 / tsc2  and  ypa1  can be rescued through treatment with the mTOR inhibitor, torin-1, and that  ypa1Δ  cells are resistant to the glycolytic inhibitor, 2-deoxyglucose. This identifies  ypa1  as a novel upstream regulator of mTOR and suggests that the effects of  ypa1  loss, together with mTOR activation, combine to result in a cellular maladaptation in energy metabolism that is profoundly inhibitory to growth.
Rayhan A, Faller A, Chevalier R, Mattice A, Karagiannis J