Abstract
Since Ronald Konopka and Seymour Benzer’s discovery of the gene Period in the 1970s, the circadian rhythm field has diligently investigated regulatory mechanisms and intracellular transcriptional and translation feedback loops involving Period, and these investigations culminated in a 2017 Nobel Prize in Physiology or Medicine for Michael W. Young, Michael Rosbash, and Jeffrey C. Hall. Although research on 24-hour behavior rhythms started with Period, a series of discoveries in the past decade have shown us that post-transcriptional regulation and protein modification, such as phosphorylation and oxidation, are alternatives ways to building a ticking clock.
Highlights
The time-keeping mechanisms of circadian rhythms can be regulated by multiple layers of different cellular networks, including transcription-translation feedback loops (TTFLs) and post-translation oscillators (PTOs)[1]
Circadian TTFLs generate oscillations in gene expression through delayed negative feedback whereby expression of a transcription factor negatively regulates its own transcription[2]. The core of this genetic network in mammals is the expression of a heterodimer of brain and muscle Arnt-like protein 1 (BMAL1) with either circadian locomotor output cycles kaput (CLOCK) or neuronal PAS domain-containing protein 2 (NPAS2), which binds at promoter cis-elements called E-boxes to drive expression of genes encoding period (PER1-3), cryptochrome (CRY1-2), and nuclear receptor subfamily (NR1D1-2) proteins, which repress Bmal[1] expression by a series of separate and interconnected feedback loops[3,4]
The most well-known PTO is the cyanobacteria KaiABC system, which consists of only three proteins and ATP7, but novel PTOs may exist in red blood cells (RBCs)[8,9,10,11,12,13,14], which lack a nucleus and the molecular machinery to drive TTFL rhythms
Summary
The time-keeping mechanisms of circadian rhythms can be regulated by multiple layers of different cellular networks, including transcription-translation feedback loops (TTFLs) and post-translation oscillators (PTOs)[1]. In S2 cells, which are generally regarded as non-rhythmic, a multi-omics approach recently revealed hundreds of genes, proteins, and metabolites with 24-hour rhythms[20] This approach seems to suggest the presence of a novel non-canonical oscillator with 24-hour periodicity, it does not preclude possible cell cycle effects from the roughly 24-hour doubling time of S2 cells or the possibility of classic circadian clock components operating below the experimental limits of detection. The anti-psychotic drug haloperidol, which selectively blocks the dopamine D2 receptor, shortens long-period rhythms induced by methamphetamine in wild-type and Bmal[1] KO mice[95] These data suggest that dopamine neurons are a second independent rhythm-generating mechanism in the brain, and future studies using chemical and genetic approaches to perturb dopamine pathways coupled with recently developed brain-clearing techniques[97,98,99,100] may enable a more complete understanding of the neural architecture of this dopamine ultradian oscillator
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
