Hypothesis The Case for the Target of Rapamycin Pathway as a Candidate Circadian Oscillator, 2023, Lakin-Thomas

[SNT Gatchaman]

The Case for the Target of Rapamycin Pathway as a Candidate Circadian Oscillator
Lakin-Thomas, Patricia

The molecular mechanisms that drive circadian (24 h) rhythmicity have been investigated for many decades, but we still do not have a complete picture of eukaryotic circadian systems. Although the transcription/translation feedback loop (TTFL) model has been the primary focus of research, there are many examples of circadian rhythms that persist when TTFLs are not functioning, and we lack any good candidates for the non-TTFL oscillators driving these rhythms.

In this hypothesis-driven review, the author brings together several lines of evidence pointing towards the Target of Rapamycin (TOR) signalling pathway as a good candidate for a non-TTFL oscillator. TOR is a ubiquitous regulator of metabolism in eukaryotes and recent focus in circadian research on connections between metabolism and rhythms makes TOR an attractive candidate oscillator.

In this paper, the evidence for a role for TOR in regulating rhythmicity is reviewed, and the advantages of TOR as a potential oscillator are discussed. Evidence for extensive feedback regulation of TOR provides potential mechanisms for a TOR-driven oscillator. Comparison with ultradian yeast metabolic cycles provides an example of a potential TOR-driven self-sustained oscillation. Unanswered questions and problems to be addressed by future research are discussed.

Link | PDF (International Journal of Molecular Sciences)

 

[SNT Gatchaman]

The mechanisms of circadian (24 h) rhythmicity have been studied in a wide variety of organisms for over 60 years, and a consensus about the molecular mechanism that drives these rhythms, at least in eukaryotes, was formulated after the cloning of clock genes in the 1980s and the publication of the transcription/translation feedback loop (TTFL) model. Decades of research have refined and broadened the TTFL concept, but there are still stubborn anomalies that challenge the TTFL model and require further development of our ideas about clock mechanisms.

In this hypothesis-driven review, my goal is to pull together several lines of evidence around a potential non-TTFL oscillator candidate and evaluate its advantages and disadvantages as a component of circadian systems in eukaryotes. The Target of Rapamycin (TOR) signalling pathway, a ubiquitous nutrient-sensing pathway in eukaryotic cells, is an attractive candidate for a non-TTFL oscillator. It is both regulated by, and a regulator of, circadian rhythmicity, and provides a link between metabolic oscillations and the TTFL.

...

More than 30 years after the TTFL model was first proposed, we still do not have a satisfactory description of the circadian system of any organism at the molecular level, except for the phosphorylation clock of cyanobacteria. Many anomalies remain unexplained, and the number of reports of non-TTFL rhythms continues to increase. There are currently no widely accepted candidates for a non-TTFL oscillator. Increasing interest in the interactions between circadian timing and metabolism puts a focus on regulators of metabolism, with the TOR pathway as a central player in metabolic control in all eukaryotes.