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Uncovering Mechanisms of the Human Biological Clock

Mechanistic understanding of the regulators of the human biological clock can provide scientists with the key to developing therapies for sleep disorders.

Human biological clocks are a network of specific molecules that interact to produce the circadian rhythm. These molecules are proteins known as clock proteins which interact with cells throughout the body. The circadian rhythm gives rise to our daily sleep and wake cycles.

A study led by scientists from Duke-NUS Medical School and the University of California Santa Cruz demonstrated how mutations in proteins are able to modify the timing of the biological clock. Mutations in these proteins that are able to shorten the biological clock timing will have a “morning lark” effect while those that make the clock run longer would cause a pronounced “night owl” effect.

“In this new study, our team focused on mutations in a protein called casein kinase 1 (CK1), which regulates a core clock protein called PERIOD (PER). Clock-altering mutations in CK1 had been known for years, but it was unclear how they changed the timing of the clock,” said Dr Rajesh Narasimamurthy, Principal Research Scientist at the Duke-NUS’ Cancer and Stem Cell Biology (CSCB) programme.

The research team performed structural and biochemical analysis of CK1 and PER proteins to discover that CK1 modifies either of two sites on the PER protein. Modification on one site stabilises PER and the other will trigger it degradation. A working molecular switch will control PER proteins to generate a 24-hour oscillation. Mutations in either CK1 or PER proteins was able to alter the balance, favouring degradation, thereby disrupting the biological clock.

“Our results provide a mechanistic foundation to understand the essentially universal role of CK1 as a regulator of eukaryotic circadian clocks. It is important to understand how these clock proteins regulate our circadian rhythms, because those rhythms affect not only the sleep cycle but almost every aspect of our physiology.” Said Professor David Virshup, Director of the Duke-NUS CSCB programme and corresponding author of this study.

Professor David highlights that understanding these molecular mechanisms may provide scientists the essentials to develop therapies for intervening in the clock to alleviate disruptions, whether they are caused by inherited conditions or by shift work or jet lag.

Further studies currently carried out by the team will investigate how CK1 activity can be modified to change the biological clock speed. These will pave the way for the search of therapies for treatment of jet lag and sleep disorders. [APBN]