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Why waking up is hard to do

NORTHWESTERN (US) — If “five more minutes” is part of your normal morning routine, you can blame it on the absence of the “twenty-four” gene—one of the core genes of the circadian clock.

The circadian clock drives, among other things, when an organism wakes up and when it sleeps. According to new research, the absence of the gene confuses the rhythm of the common fruit fly’s sleep-wake cycle, making it harder for the flies to wake up.

The research, published in the journal Nature, has implications for humans.

“The function of a clock is to tell your system to be prepared, that the sun is rising, and it’s time to get up,” says Ravi Allada, professor of neurobiology and physiology at Northwestern University.

“The flies without the twenty-four gene did not become much more active before dawn. The equivalent in humans would be someone who has trouble getting out of bed in the morning.”

Period (per) is a gene in fruit flies that encodes a protein, called PER, which regulates circadian rhythm. Twenty-four is critically important to producing this key clock protein—when it isn’t present, very little PER protein is found in the neurons of the brain, and the fly’s sleep-wake rhythm is disturbed.

It seems it was fate that the gene would be important in regulating the 24-hour sleep-wake cycle. The gene’s generic name is CG4857, and the numbers add up to 24, earning it the twenty-four nickname. (The fruit fly’s genome was sequenced in 2000, but until now the function of this gene was unknown.)

The known core mechanisms of the circadian clock, both in flies and humans, involve the process of transcription, where RNA is produced from DNA. A portion of the control system called a transcriptional feedback loop also is important.

In trying to identify new clock components, a new player in the system was identified, the gene twenty-four. But instead of operating in the process of transcription, it operates in the process of translation: translating proteins from RNA.

Twenty-four appears to be a protein that promotes translation of period RNA to protein.

“This really defines a new mechanism by which circadian clocks are functioning,” Allada says. “We found that twenty-four has a really strong and critical role in translating a key clock protein. Translation really wasn’t appreciated before as having such an important role in the process.”

The researchers believe it is likely that a mechanism similar to that described for the fly gene twenty-four will be evolutionarily conserved and found in humans.

Working with scientists at the Korea Advanced Institute of Science and Technology (KAIST), Allada used a Drosophila library at KAIST to screen the behavior of 4,000 different flies looking for flies whose sleep-wake cycles were awry.

Each fly had a different overexpressed gene and thus different behavior. The fly with the most dramatic change was one with a longer cycle than normal, 26 hours instead of 24.

The overexpressed gene in this fly was CG4857, which was then removed, or knocked out in the flies. These flies had poor sleep-wake rhythm and would sleep and wake at all times of day.

The researchers found very little of the critical PER protein in the brain neurons despite the fact that per RNA is likely produced in the neurons. Without twenty-four the RNA was not translated into the PER protein, leading to dysfunction.

The study was supported by the  National Institutes of Health and the National Research Foundation of Korea.

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