A tti1 mutation in the Tel2-Tti1-Tti2 complex specifically eliminates the cellular function of Rad3ATR, but not that of other PIKKs in fission yeast

The Tel2-Tti1-Tti2, or TTT complex, is the co-chaperone for co-translational maturation of all phosphatidylinositol 3-kinase-related kinases (PIKKs). The complex is highly conserved in eukaryotes and controls multiple cellular processes through PIKKs. Mutations of the TTT complex have recently been linked to disease syndromes and cancer. In Schizosaccharomyces pombe , six PIKKs are expressed: Rad3 ATR , Tel1 ATM , Tor1 and Tor2 (homologs of mTOR), and Tra1 and Tra2 (homologs of TRRAP). While Rad3 ATR and Tel1 ATM are the central cell-cycle checkpoint kinases in response to DNA damage and replication stress, the other four PIKKs govern cell growth, nutrient sensing, and transcriptional regulation. Here, we report the identification of seven tti1 mutants in fission yeast that are sensitive to genotoxins. Characterization of one of the mutants, tti1-N18 , reveals that the mutation selectively eliminates the kinase function of Rad3 ATR , but not that of Tel1 ATM . Further examination shows that, like Tel1 ATM , the functions of the other four PIKKs are also largely uncompromised in the tti1-N18 mutant. These findings suggest a mechanism by which the TTT complex confers functional specificity towards Rad3 ATR among the PIKKs. Since human Tel2 has been identified as a target of the antiparasitic drug Ivermectin, further investigation of the substrate specificity of the TTT complex may reveal a therapeutic vulnerability for treatment of cancer or other diseases.