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Researcher have uncovered just what keeps our internal clock ticking. 

They say two genes – Period and Cryptochrome – keep the circadian clocks in all human cells in time and in proper rhythm with the 24-hour day, as well as the seasons.  

The finding has major implications for the development of drugs for diseases such as cancers and diabetes, as well as conditions such as metabolic syndrome, insomnia, seasonal affective disorder, obesity, and even jetlag.

The discovery could mean more effective treatments for jetlag and other sleep disorders

'Discovering how these circadian clock genes interact has been a long-time coming,' said Aziz Sancar, MD, PhD, Sarah Graham Kenan Professor of Biochemistry and Biophysics and senior author of the Genes and Development paper. 

'We've known for a while that four proteins were involved in generating daily rhythmicity but not exactly what they did. 

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.'

In all human cells, there are four genes – Cryptochrome, Period, CLOCK, and BMAL1 – that work in unison to control the cyclical changes in human physiology, such as blood pressure, body temperature, and rest-sleep cycles.

Previously, scientists found that CLOCK and BMAL1 work in tandem to kick start the circadian clock. 

These genes bind to many other genes and turn them on to express proteins. 

This allows cells, such as brain cells, to behave the way we need them to at the start of a day.

Specifically, CLOCK and BMAL1 bind to a pair of genes called Period and Cryptochrome and turn them on to express proteins, which – after several modifications – wind up suppressing CLOCK and BMAL1 activity. 

The breakthrough could lead to new treatments for jetlag, insomnia and other sleep disorders

Then, the Period and Cryptochrome proteins are degraded, allowing for the circadian clock to begin again.

'It's a feedback loop,' said Sancar, who discovered Cryptochrome in 1998. 

'The inhibition takes 24 hours. 

'This is why we can see gene activity go up and then down throughout the day.'

'What we've done is show how the entire clock really works,' Sancar said. 

'Now, when we screen for drugs that target these proteins, we know to expect different outcomes and why we get those outcomes. 

Whether it's for treatment of jetlag or seasonal affective disorder or for controlling and optimizing cancer treatments, we had to know exactly how this clock worked.'

Previous to this research, in 2010, Sancar's lab found that the level of an enzyme called XPA increased and decreased in synchrony with the circadian clock's natural oscillations throughout the day. 

Sancar's team proposed that chemotherapy would be most effective when XPA is at its lowest level. For humans, that's late in the afternoon.

'This means that DNA repair is controlled by the circadian clock,' Sancar said. 

'It also means that the circadian clocks in cancer cells could become targets for cancer drugs in order to make other therapeutics more effective.'