Three Genes Essential for Cells to Tell Time

Summary: Researchers have identified three new genes associated with circadian rhythm regulation.

Source: University of Tokyo.

One family of genes allows cells to adapt to daily changes in environmental conditions by adjusting their internal “body clock,” the circadian clock responsible for regular sleep-wake cycles. The new discovery by University of Tokyo scientists reveals for the first time that circadian regulation may be directly connected to cellular stress.

Circadian rhythms are found in almost all organisms with sensitivity to light. Problems with circadian rhythms in humans are related to diseases including high blood pressure (hypertension), metabolic disorders, and insomnia. Shift workers and the elderly both have increased risk for these diseases as a result of disruption of their circadian clock.

The research team responsible for the work is based at the University of Tokyo and led by Professor Yoshitaka Fukada and Assistant Professor Hikari Yoshitane in the Department of Biological Sciences. The latest results stem from a series of ongoing experiments and continue to build on the lab’s interests in circadian studies. Collaborators led by Professor Hidenori Ichijo of the Graduate School of Pharmaceutical Sciences developed the unique mice used in the experiments.

Researchers used cells and mice that lacked three genes: apoptosis signal-regulating kinase 1, 2, and 3 (Ask1, Ask2, Ask3). In results from both cells and mice, the Ask genes were necessary to respond to both sudden changes to the environment and gradual changes over time.

Cells without the Ask genes did not show the changes to their circadian rhythm that are expected from normal cells growing in environments with too high or too low salt or sugar concentrations. The cells without Ask genes were also impervious to the changes expected after cells accumulate too much oxidative stress. Uncontrolled oxidative stress creates potentially toxic environments within cells due to changes in chemical balance.

“Many researchers in this field have long suspected oxidative stress and circadian rhythms are somehow connected because of the cycles of photosynthesis and DNA replication we see even in ancient organisms; photosynthesis requires sunlight and creates free radicals that could damage DNA, so cells postpone DNA replication and cell division until nighttime when photosynthesis has stopped. We are very excited about our results because we can approach the origin of the circadian clock by connecting oxidative stress and circadian regulation through the Ask genes,” said Fukada.

Researchers used cells and mice that lacked three genes: apoptosis signal-regulating kinase 1, 2, and 3 (Ask1, Ask2, Ask3). In results from both cells and mice, the Ask genes were necessary to respond to both sudden changes to the environment and gradual changes over time. image is in the public domain.

The results in cells were further supported by observations of mouse behavior. Normal mice can change their wake-up time the next morning after unexpected light exposure during the night, as measured by their activity running on a wheel. Mice without Ask genes have less ability to synchronize their circadian clock to changes in environmental light-dark cycles.

“The dream is to have a tool to regulate circadian rhythms. Basic science like our research can show hints for later drug discovery work,” said Yoshitane.

The University of Tokyo team plans to continue to study the detailed cellular mechanisms connecting Ask genes to oxidative stress and potential methods of influencing the circadian rhythm.

About this neuroscience research article

Funding: Japan Society for the Promotion of Science research fellowship for young scientists Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology PRIME, the Japan Agency for Medical Research and Development.

Source: Junko Taniai – University of Tokyo
Publisher: Organized by
Image Source: image is in the public domain.
Original Research: Open access research in PNAS.

Cite This Article

[cbtabs][cbtab title=”MLA”]University of Tokyo “Three Genes Essential for Cells to Tell Time.” NeuroscienceNews. NeuroscienceNews, 19 March 2018.
<>.[/cbtab][cbtab title=”APA”]University of Tokyo (2018, March 19). Three Genes Essential for Cells to Tell Time. NeuroscienceNews. Retrieved March 19, 2018 from[/cbtab][cbtab title=”Chicago”]University of Tokyo “Three Genes Essential for Cells to Tell Time.” (accessed March 19, 2018).[/cbtab][/cbtabs]


ASK family kinases mediate cellular stress and redox signaling to circadian clock

Daily rhythms of behaviors and physiologies are generated by the circadian clock, which is composed of clock genes and the encoded proteins forming transcriptional/translational feedback loops (TTFLs). The circadian clock is a self-sustained oscillator and flexibly responds to various time cues to synchronize with environmental 24-h cycles. However, the key molecule that transmits cellular stress to the circadian clockwork is unknown. Here we identified apoptosis signal-regulating kinase (ASK), a member of the MAPKKK family, as an essential mediator determining the circadian period and phase of cultured cells in response to osmotic changes of the medium. The physiological impact of ASK signaling was demonstrated by a response of the clock to changes in intracellular redox states. Intriguingly, the TTFLs drive rhythmic expression of Ask genes, indicating ASK-mediated association of the TTFLs with intracellular redox. In behavioral analysis, Ask1, Ask2, and Ask3 triple-KO mice exhibited compromised light responses of the circadian period and phase in their activity rhythms. LC-MS/MS–based proteomic analysis identified a series of ASK-dependent and osmotic stress-responsive phosphorylations of proteins, among which CLOCK, a key component of the molecular clockwork, was phosphorylated at Thr843 or Ser845 in the carboxyl-terminal region. These findings reveal the ASK-dependent stress response as an underlying mechanism of circadian clock flexibility.

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