Crosstalk between the mTOR and DNA Damage Response Pathways in Fission Yeast

Abstract

Cells have developed response systems to constantly monitor environmental changes and accordingly adjust growth, differentiation, and cellular stress programs. The evolutionarily conserved, nutrient-responsive, mechanistic target of rapamycin signaling (mTOR) pathway coordinates basic anabolic and catabolic cellular processes such as gene transcription, protein translation, autophagy, and metabolism, and is directly implicated in cellular and organismal aging as well as age-related diseases. mTOR mediates these processes in response to a broad range of inputs such as oxygen, amino acids, hormones, and energy levels, as well as stresses, including DNA damage. Here, we briefly summarize data relating to the interplays of the mTOR pathway with DNA damage response pathways in fission yeast, a favorite model in cell biology, and how these interactions shape cell decisions, growth, and cell-cycle progression. We, especially, comment on the roles of caffeine-mediated DNA-damage override. Understanding the biology of nutrient response, DNA damage and related pharmacological treatments can lead to the design of interventions towards improved cellular and organismal fitness, health, and survival.

Keywords: Rad3; TORC1; TORC2; caffeine; nutrients; rapamycin.

Figure 1

Schizosaccharomyces pombe and human TORC1 and TORC2 complexes. Each complex is composed by a TOR kinase (predominantly Tor2 for TORC1 and Tor1 for TORC2 fission yeast complexes) and at least four partners identified through mass spectrometry approaches. Lst8 is a common partner for both TORC1 and TORC2. However, in fission yeast, Mip1 (RAPTOR), Tco89, and Toc1 are associated with TORC1 only, while Ste20 (RICTOR), Sin1, and Bit61 are associated with TORC2. In human complexes, DEPTOR is found in both complexes, while PRAS40 is associated with TORC1 and PRR5/PRR5L with TORC2. Each complex has pivotal roles in metabolism, cell organization, growth, and survival (see main text for details). mTOR, mechanistic target of rapamycin.

Figure 2

Interaction of DNA damage response (DDR), environmental stress response (ESR), and TORC1/TORC2 signaling in S. pombe. TORC1 and TORC2 play distinct roles in regulating cell growth and division as well as responses to environmental stresses and nutrient availability. Activation of Rad3 by DNA damage or replication stress leads to the activation of Chk1 and Cds1, respectively. Chk1 and Cds1 inhibit Cdc25 and activate Wee1 (or Mik1) to inhibit Cdc2 and delay cell cycle progression. Direct inhibition drives cells into mitosis via the Ppk18-Igo1-PP2A^Pab1 pathway in the presence of DNA damage, suggesting Rad3 may maintain TORC1 activity during cell cycle arrest. Conversely, TORC2 is required for the resumption of cell cycle progression once DNA repair has been affected. Rad3 may also regulate TORC2 activity during the DDR. Caffeine may directly inhibit TORC1 as a low affinity ATP competitor. Alternatively, caffeine may indirectly inhibit TORC1 via activation of the ESR and Ssp1-Ssp2 (AMPK) pathways.