TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions.
The Target Of Rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol-3-kinase-related kinases (PIKKs). TOR proteins are found at the core of two distinct evolutionarily conserved complexes, TORC1 and TORC2. Disruption of TORC1 or TORC2 results in characteristically dissimilar phenotypes. TORC1 is a major cell growth regulator, while the cellular roles of TORC2 are not well understood. In the fission yeast Schizosaccharomyces pombe, Tor1 is a component of the TORC2 complex, which is particularly required during starvation and various stress conditions. Our genome-wide gene expression analysis of Deltator1 mutants indicates an extensive similarity with chromatin structure mutants. Consistently, TORC2 regulates several chromatin-mediated functions, including gene silencing, telomere length maintenance, and tolerance to DNA damage. These novel cellular roles of TORC2 are rapamycin insensitive. Cells lacking Tor1 are highly sensitive to the DNA-damaging drugs hydroxyurea (HU) and methyl methanesulfonate, similar to mutants of the checkpoint kinase Rad3 (ATR). Unlike Rad3, Tor1 is not required for the cell cycle arrest in the presence of damaged DNA. Instead, Tor1 becomes essential for dephosphorylation and reactivation of the cyclin-dependent kinase Cdc2, thus allowing reentry into mitosis following recovery from DNA replication arrest. Taken together, our data highlight critical roles for TORC2 in chromatin metabolism and in promoting mitotic entry, most notably after recovery from DNA-damaging conditions. These data place TOR proteins in line with other PIKK members, such as ATM and ATR, as guardians of genome stability.
Schonbrun
Miriam
M
Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel-Aviv, Israel.
Laor
Dana
D
López-Maury
Luis
L
Bähler
Jürg
J
Kupiec
Martin
M
Weisman
Ronit
R
D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D004249:DNA Damage; D004261:DNA Replication; D004789:Enzyme Activation; D015966:Gene Expression Regulation, Fungal; D020868:Gene Silencing; D006918:Hydroxyurea / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism; D009153:Mutagens / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*
D046912:Multiprotein Complexes; D009153:Mutagens; D019384:Nucleic Acid Synthesis Inhibitors; D029702:Schizosaccharomyces pombe Proteins; D008741:Methyl Methanesulfonate; D011494:Protein Kinases; C523461:Tor1 protein, S pombe; D016203:CDC2 Protein Kinase; C469447:cdc2 protein, S pombe; D006918:Hydroxyurea