Dartmouth Medical School geneticists have discovered a new class of proteins that see light, revealing a previously unknown system for how light works.

The novel photoreceptors are part of the gears that drive biological clocks, the cellular timekeepers of the circadian rhythm, which paces life's daily ebb and flow in a 24-hour light-dark cycle. Their identification also opens a window for genetically engineered drug delivery systems that exploit the properties of these newfound molecules.

The findings, by Drs. Jay Dunlap and Jennifer Loros, and graduate student Allan Froehlich, will be published in an upcoming issue of Science; they are currently reported online in Science Express.

Dunlap, professor and chair of genetics, and Loros, professor of biochemistry, were the first to delineate circadian clockwork in Neurospora, the common bread mold and one of the best-known genetic model systems. They pieced together how the circadian cycle works and demonstrated how light resets it through a complex of interwoven molecular messages.

"That left open the question then of what actually absorbed the light. What we found is a new paradigm within clocks," Dunlap says. "Light is absorbed by a molecule that is actually within the clock and is an activating element in the clock cycle. This is a new molecular mechanism to see light and a new way for light to have an effect. Although the protein has been known for sometime, this is a configuration of activities that's not been reported before for any protein."

Since bread mold belongs to the fungal phylogenetic kingdom, eventually researchers may be able to harness the proteins against fungal disease. "Virtually nothing is known about how pathogenic fungi respond to light or whether that can be exploited for a noninvasive therapy," Dunlap acknowledges. It may be a long shot, but drug therapies start with properties people don't have. "If you want to do therapy--antifungal, antibacterial or anything--you start looking for biochemical activities that the host does not have that can be targeted on the pathogen."

Froelich, a graduate student with Dunlap and Loros, built on their discovery that the gene frequency (frq) encodes a central cog of the clock cycle and that light resets the clock by acting on frq. He identified the frq parts necessary and sufficient for light induced expression of the gene, and determined that the proteins that bind to these parts are the clock proteins White Collar-1 and White Collar-2 (WC-1 and WC-2). He then showed that both proteins were sufficient for binding, that under appropriate biochemical conditions they could also detect light and, subsequently, that WC-1 is actually the photoreceptor protein.

WC-1 is a transcription factor that partners with WC-2, and binds to DNA of light-regulated genes. Transcription factors are proteins whose role is to regulate expression of genes; they bind to DNA and turn on genes, Dunlap explains. "This is the first case of a transcription factor that is itself a photo pigment and a transcription factor that contains both ability to turn on gene expression and ability to do that in response to light within the same protein."

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For further information, contact Jay Dunlap at: http://Jay.Dunlap@dartmouth.edu/.

Contact: DMS Communications, dms.communications@dartmouth.edu, 603-650-1492, Dartmouth Medical School

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