» Articles » PMID: 27172216

Saccharomyces Cerevisiae Tti2 Regulates PIKK Proteins and Stress Response

Overview
Journal G3 (Bethesda)
Date 2016 May 13
PMID 27172216
Citations 15
Authors
Affiliations
Soon will be listed here.
Abstract

The TTT complex is composed of the three essential proteins Tel2, Tti1, and Tti2 The complex is required to maintain steady state levels of phosphatidylinositol 3-kinase-related kinase (PIKK) proteins, including mTOR, ATM/Tel1, ATR/Mec1, and TRRAP/Tra1, all of which serve as regulators of critical cell signaling pathways. Due to their association with heat shock proteins, and with newly synthesized PIKK peptides, components of the TTT complex may act as cochaperones. Here, we analyze the consequences of depleting the cellular level of Tti2 in Saccharomyces cerevisiae We show that yeast expressing low levels of Tti2 are viable under optimal growth conditions, but the cells are sensitive to a number of stress conditions that involve PIKK pathways. In agreement with this, depleting Tti2 levels decreased expression of Tra1, Mec1, and Tor1, affected their localization and inhibited the stress responses in which these molecules are involved. Tti2 expression was not increased during heat shock, implying that it does not play a general role in the heat shock response. However, steady state levels of Hsp42 increase when Tti2 is depleted, and tti2L187P has a synthetic interaction with exon 1 of the human Huntingtin gene containing a 103 residue polyQ sequence, suggesting a general role in protein quality control. We also find that overexpressing Hsp90 or its cochaperones is synthetic lethal when Tti2 is depleted, an effect possibly due to imbalanced stoichiometry of a complex required for PIKK assembly. These results indicate that Tti2 does not act as a general chaperone, but may have a specialized function in PIKK folding and/or complex assembly.

Citing Articles

A proteome-wide yeast degron collection for the dynamic study of protein function.

Valenti R, David Y, Edilbi D, Dubreuil B, Boshnakovska A, Asraf Y J Cell Biol. 2024; 224(2).

PMID: 39692734 PMC: 11654244. DOI: 10.1083/jcb.202409050.


Mistranslating the genetic code with leucine in yeast and mammalian cells.

Davey-Young J, Hasan F, Tennakoon R, Rozik P, Moore H, Hall P RNA Biol. 2024; 21(1):1-23.

PMID: 38629491 PMC: 11028032. DOI: 10.1080/15476286.2024.2340297.


TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.

Bhadra S, Xu Y Int J Mol Sci. 2023; 24(9).

PMID: 37175973 PMC: 10178989. DOI: 10.3390/ijms24098268.


The Role of Hsp90-R2TP in Macromolecular Complex Assembly and Stabilization.

Lynham J, Houry W Biomolecules. 2022; 12(8).

PMID: 36008939 PMC: 9406135. DOI: 10.3390/biom12081045.


Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.

Senko A, Overall R, Silhavy J, Mlejnek P, Malinska H, Huttl M PLoS Genet. 2022; 18(4):e1009638.

PMID: 35377872 PMC: 9060359. DOI: 10.1371/journal.pgen.1009638.


References
1.
Brown C, Dalphin M, Stockwell P, Tate W . The translational termination signal database. Nucleic Acids Res. 1993; 21(13):3119-23. PMC: 309741. DOI: 10.1093/nar/21.13.3119. View

2.
Kopczynski J, Raff A, Bonner J . Translational readthrough at nonsense mutations in the HSF1 gene of Saccharomyces cerevisiae. Mol Gen Genet. 1992; 234(3):369-78. DOI: 10.1007/BF00538696. View

3.
Parsell D, Kowal A, Singer M, Lindquist S . Protein disaggregation mediated by heat-shock protein Hsp104. Nature. 1994; 372(6505):475-8. DOI: 10.1038/372475a0. View

4.
Runge K, Zakian V . TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae. Mol Cell Biol. 1996; 16(6):3094-105. PMC: 231304. DOI: 10.1128/MCB.16.6.3094. View

5.
Cross F . 'Marker swap' plasmids: convenient tools for budding yeast molecular genetics. Yeast. 1997; 13(7):647-53. DOI: 10.1002/(SICI)1097-0061(19970615)13:7<647::AID-YEA115>3.0.CO;2-#. View