Fitting the Final Pieces in the Circadian Clock Puzzle


How do the circadian clock genes operate to generate and maintain the daily and seasonal rhythmicity in human cells? The final pieces of this puzzle have now fallen into place with research findings from the UNC’s School of Medicine.


The finding (published in the journal Genes and Development) could have far reaching implications. “We’ve known for a while that four proteins were involved in generating daily rhythmicity but not exactly what they did”, say Aziz Sancar and Sarah Graham Kenan, senior authors of the paper. “Now we know how the clock is reset in all cells. So we have a better idea of what to expect if we target these proteins with therapeutics.”


The four genes – Cryptochrome, Period, CLOCK, and BMAL1 – are known to work in a well-orchestrated feedback loop of protein expression and suppression to allow body cells kick-start and wind down the circadian clock. How exactly this happens at the back end was the mystery.


Researchers at Sancar’s lab at the UNC School of Medicine have now shown how the entire clock really works. On a well-founded assumption that the two genes Cryptochrome and Period may have complementary roles in this cycle, they conducted experiments to selectively remove and add the two genes to unfold the picture in its entirety.


This is a huge step in the development of drugs for various diseases such as cancers and diabetes, as well as conditions such as metabolic syndrome, insomnia, seasonal affective disorder, obesity, and even jetlag. Says Dr Sancar, “Now, when we screen for drugs that target these proteins, we know to expect different outcomes and why we get those outcomes…Circadian clocks in cancer cells could become targets for cancer drugs to make other therapeutics more effective.”


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