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The world first in manipulating the daily clock

The Nagoya University Institute of Transformational Biomolecules (WPI-ITbM) research team consisting of Associate Designated Professor Tsuyoshi Hirota, Postdoctoral Fellow Simon Miller, Professor Kenichiro Itami and Graduate Student Tsuyoshi Oshima (Research Fellowship for Young Scientists, JSPS), in collaboration with Professor Ben’s group investigated Veringa and a postdoctoral fellow, Dushan Kurarsky of the University of Groningen in the Netherlands, ranked first in the world: a completely reversible manipulation of the circadian rhythm using light, by replacing a portion of a compound with a photoactivation switch.

Waking up in the morning and sleeping at night – the majority of our biological activities are repeated in a daily cycle. The internal process that governs this rhythm is known as a biological clock. While it is understood that the biological clock is controlled by the shared functions of clock genes and clock proteins, the process by which rhythm can be controlled and stabilized over a long period of the day is shrouded in mystery. In order to address this question, the researchers created a biochemical process to extensively analyze the effects of the compounds on the circadian rhythm in cultured human cells, and to explain the important molecular mechanisms that determine the daily period.

This large-scale chemical assay identified two compounds – TH303 and its TH129 analogs – which prolonged the circadian rhythm. The research team then worked to elucidate how these compounds interact with CRY1 at the molecular level using X-ray crystallography. They found that a part of these compounds, known as benzophenone, possesses a structure similar to the cis isomer of azobenzene, a switch that works with light. When they next analyzed the response to GO1323 light, a variant of TH129 in which benzophenone is displaced by isobenzene, they found that its structure changed to the cis isomer under ultraviolet light, and back to the trans isomer under white light. According to computer simulations, the cis isomer of GO1323 reacts similarly to TH129 with CRY1, while the trans isomer does not interact with it.

Thus, on exposure to ultraviolet light, the daily hourly period was extended for cultured human cells treated with GO1323 compared to those kept in the dark. Moreover, upon exposure to white light, the daily clock period of these cells returned to normal, proving that the process is reversible. Since ultraviolet light damages cells, the research team had to find a way to adapt the process to use a harmless region of the spectrum to extend the period. They synthesized GO1423, which contains tetrafluorobenzene. This compound changes to the cis isomer under green light, and to the trans isomer under the violet light, while maintaining other desired properties of GO1323. When cells treated with GO1423 were exposed to green light, their circadian rhythm period was extended compared to those that remained in the dark, and when exposed to violet light, the effect was reversed. Thus researchers have succeeded in producing a reversible method for controlling the circadian rhythm using visible light.

It is expected that controlling the daily clock using methods such as these will contribute to treating related diseases such as sleep disorders, metabolic syndrome and cancer, and this research achievement represents an important and exciting step forward in this field.

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