Studies Link Circadian Rhythm, Metabolism, Longevity to One Protein

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Key to that fluctuation is the so-called molecular clock. At the heart of the clock mechanism are two proteins, CLOCK and BMAL1. These two proteins interact to form a complex that binds to DNA to activate the expression of several other circadian genes, including Period (PER) and cryptochrome (CRY). It takes a while for PER and CRY proteins to accumulate, but once they do (by late afternoon), they form a complex that blocks CLOCK and BMAL1 activity. PER and CRY expression then stops (because CLOCK/BMAL1 activity turns the genes on), and the PER and CRY proteins slowly degrade, allowing the clock to reset itself. This entire process occurs over about 24 hours, hence, a circadian rhythm.

Interestingly, CLOCK does more than bind DNA. It also functions as an enzyme that catalyzes the transfer of a small molecular mark (an acetyl group) to certain proteins, thereby changing their activities, much like flipping a switch. One of those targets is BMAL1.

Sassone-Corsi reasoned that for every enzyme that can add a molecular mark, there must be another that can remove it. "That's the way biology works; there is yin and yang to any function in the cell," he said.

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His search led him to SIRT1, an enzyme that is responsive to metabolism and that requires, among other things, a molecule called nicotinamide adenine dinucleotide (NAD) to function. Because NAD levels fluctuate with the cell's metabolic state, SIRT1 is likewise responsive to metabolism.

"The key finding [for both papers is] that SIRT1 is a deacetylase involved in regulating circadian biology," said Sassone-Corsi. "And because SIRT1 is regulated by NAD, it links metabolism with circadian rhythms."

Schibler's team arrived at the same conclusion from a completely different angle. Recognizing that feeding cycles are critical to synchronizing the molecular clock, Schibler reasoned there must be a clock component capable of sensing metabolic state. As NAD seemed a good candidate for such a sensor, he looked specifically at NAD-binding proteins.

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