Researchers Identify New Component Of Circadian Clock

June 05, 1998


Protein Involved In Activation Of Circadian Rhythm Genes

BOSTON--June 1, 1998--Researchers at Harvard Medical School have identified a protein that partners with the mammalian CLOCK protein to regulate circadian rhythms. Together, the two proteins appear to induce transcription of circadian rhythm genes. Their findings are published in the June 5 Science.

The daily, or circadian, rhythms of fruit flies--and presumably of mammals as well--are driven by the switching on and off of genes in a handful of cells. Per is one gene known to be an integral part of the molecular clock of flies. Researchers have also identified mammalian genes similar to per.

When the per gene is switched on, it initiates the synthesis of messenger RNA. The mRNA is then dispatched outside the nucleus, where the Per protein is made. Per protein gradually accumulates in the cell for several hours and then, at some it moves swiftly into the nucleus, shutting off its own gene and ending the circadian cycle. Until now, it was unclear what turned on per.

Last year, researchers at Northwestern University identified the first mammalian circadian gene in mice, which they named Clock. Mice with mutated Clock genes have disrupted rest and activity patterns. But it was unclear how CLOCK, the protein encoded by this gene, controlled circadian rhythms.

Charles Weitz, HMS assistant professor of neurobiology, and his colleagues suspected that CLOCK might be involved in the transcriptional activation of the mammalian per gene and most likely needed a partner to do the job. They identified a protein that interacts with CLOCK, named BMAL1, and found that BMAL1 and CLOCK bind to transcription factor sites near one of the mammalian per genes, producing an increase in transcriptional activity. BMAL1 and the mutant version of CLOCK also bound to the same sites, but no transcriptional activity resulted.

"These findings tie together Clock, which has been genetically proven to be a component of the circadian system, with the mammalian version of per, which is likely to be part of the clock based on its similarity to the fly gene," says Weitz.

In a related paper in the same issue of Science, Steven Kay of the Scripps Research Institute, Weitz, and their colleagues show that the fly version of CLOCK--together with the fly version of BMAL1 identified by Weitz's team--induces transcription of per, showing how closely conserved genes are between different organisms.

Next, Weitz and his colleagues hope to shed light on the negative feedback part of the circadian loop, identifying how per and timeless interfere with the action of Clock and BMAL1. "Solving that problem would give us a view of one complete turn of the circadian clock," says Weitz.
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Harvard Medical School

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