Genetic suppressor screen identifies Tgp1 (glycerophosphocholine transporter), Kcs1 (IP 6  kinase), and Plc1 (phospholipase C) as determinants of inositol pyrophosphate toxicosis in fission yeast.
The inositol pyrophosphate metabolite 1,5-IP 8  governs repression of fission yeast phosphate homeostasis genes  pho1 ,  pho84 , and  tgp1  by lncRNA-mediated transcriptional interference. Asp1 pyrophosphatase mutations that increase IP 8  levels elicit precocious lncRNA termination, leading to derepression of the  PHO  genes. Deletions of the Asp1 pyrophosphatase domain result in growth impairment or lethality via IP 8  agonism of transcription termination. It was assumed that IP 8  toxicity ensues from dysregulation of essential genes. In this study, a suppressor screen revealed that IP 8  toxicosis of Asp1 pyrophosphatase mutants is caused by: (i) a >40-fold increase in the expression of the inessential  tgp1  gene encoding a glycerophosphodiester transporter and (ii) the presence of glycerophosphocholine in the growth medium. The suppressor screen yielded missense mutations in two upstream enzymes of inositol polyphosphate metabolism: the phospholipase C enzyme Plc1 that generates IP 3  and the essential Kcs1 kinase that converts IP 6  to 5-IP 7 , the immediate precursor of IP 8 .
Bednor L, Sanchez AM, Garg A, Shuman S, Schwer B