Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe

Abstract

Rapamycin and its derivatives have now emerged as an attractive therapeutic strategy with both immunosuppressant and antitumor properties. In addition, rapamycin has been proposed as a calorie restriction mimetic to extend the life span of various organisms. The fission yeast Schizosaccharomyces pombe (S. pombe) serves as a valuable genetic model system to study the mechanism(s) of drug action as well as to determine genetic contexts associated with drug sensitivity or resistance. Here, we identified genes that when deleted modulate the rapamycinsensitive strains in S. pombe. We carried out a chemical genomics screen for rapamycin-sensitive mutants using the genome-deletion library which covers 95.3% of all nonessential fission yeast genes and confirmed 59 genes to be rapamycin sensitive. Gene Ontology (GO) enrichment analysis showed that strains sensitive to rapamycin are highly enriched in processes regulating tRNA modification and mitochondria as well as other ontologies, including cellular metabolic process, chromatin organization, cell cycle, signaling, translation, transport and other cellular processes. Analysis also showed that components of the Elongator complex are overrepresented in the sensitive strains. Here, the data obtained will provide valuable information for speculation on the actions of rapamycin as well as on TORC signaling, thereby presenting a strategy to enhance sensitivity to rapamycin.

Genetic defects in SAPK signalling, chromatin regulation, vesicle transport and CoA-related lipid metabolism are rescued by rapamycin in fission yeast

“…Previously, large-scale screening of yeast deletion libraries has been conducted to test rapamycin sensitivity [ 46 , 47 ]. Genes affecting rapamycin sensitivity are mainly involved in upregulation of TOR signalling, as gene deletions cause hypersensitivity to rapamycin.…”

The multistress‐induced Translocator protein (TSPO) differentially modulates storage lipids metabolism in seeds and seedlings

“…We took advantage of the fact that the fission yeast genome encodes (SPBC725.10) and expresses a TSPO protein (here after called SpTSPO). Interestingly, SPBC725.10 is upregulated during nitrogen starvation and its deletion (strain ΔSPBC725.10) enhances sensitivity to the autophagy‐inducible drug rapamycin (Doi et al ., ), and its overexpression increases viability at the stationary growth phase (Ohtsuka et al ., ). We first confirmed by PCR that the SPBC725.10 locus was indeed disrupted in strain ΔSPBC725.10 (Figure a).…”

The fission yeast Greatwall–Endosulfine pathway is required for proper quiescence/G0 phase entry and maintenance

“…Our observation is consistent with that of their study. Control of TORC1 activity is central to cellular nutritional regulations that have medical importance and thus has been intensively studied using various organisms (Chia et al, 2017;Doi et al, 2015;Kamada, 2017;Nakase et al, 2006;Otsubo, Nakashima, Yamamoto, & Yamashita, 2017;Saxton & Sabatini, 2017;Tanigawa & Maeda, 2017;Uritani et al, 2006).…”