Hanover, NH -- Dartmouth Medical School geneticists have clarified the picture of the way living things maintain robust and stable internal clocks to safeguard the timing of daily activities.
Internal clocks are ubiquitous. In humans they cue circadian rhythms, the 24-hour cycle that paces life's ebb and flow, from when we wake up to when we go to sleep. They are linked to jet lag, seasonal affective disorder and sleep disturbances.
Research published in the July 7 issue of Science delineates the dual roles and interlocking connections of the molecular gears that drive biological clocks and prevent them from winding down. The striking parallels in a relatively simple model offer clues to what makes creatures tick, report the DMS authors -- Jay Dunlap, professor and chair of genetics, Jennifer Loros, professor of biochemistry, and Kwangwon Lee, a postdoctoral fellow.
Just as the machinery behind clock faces of countless shapes and designs is built on a few basic principles, the genetic machinery behind all biological clocks -- from plants to people -- shares fundamental properties, in spite of the diverse functions governed. Studying the development of spores in the bread mold Neurospora, Dunlap and Loros have teased apart the genetic cogs that form the basis of most living clocks. Light and dark cycles reset the clocks, they found, the way turning the hands of a clock does, but are not required to run them.
The recent announcement that a map of the human genome is nearly complete propels research into a new era of identifying, treating and -preventing problems. "The human genome is a parts list. Now we have a description: how big, what shape, maybe where the part -- or gene -- is located, and sometimes, with all this information, we can infer what it does," explains Dunlap. "Still, first we have to know what to look for."
In an experimental system such as bread mold, which is a fungus, scientists can identify the gene, pull it out and further explore it. They can decipher the sequence of its chemical units and determine how it acts. From his studies, Dunlap says, "we see what proteins might be good candidates for genes that might be mutated in sleep disorders and where to start looking."
The clock mechanism, called an oscillator, is a delicate balancing act of chemical messages where protein products feed back to shut off their own gene activity. If clocks operated solely on negative feedback delay, they would run down quickly, Dunlap explains.
The current report details the opposing dualities and complex interplay among the Neurospora clock genes and proteins they produce in the intricate feedback loops that keep time. The relationships among the components, not the absolute levels, set internal time.
The clock cycle involves a central cog, the Frequency (FRQ) protein, and a complex, called white collar proteins, that control behavior in both light and dark phases. The DMS research reveals more dexterity than once thought. FRQ has dual functions, blocking some products while promoting synthesis of others, depending on the white collar protein signals. "What we thought was a negative is actually positive as well," says Dunlap.
In addition, stretches of the white collar proteins resemble those of comparable regulatory proteins in mice and humans. "The wiring is similar, although the molecular biology -- at the level of making protein -- is different," notes Dunlap. "Sequence conservation between proteins has evolutionary importance and indicates the extent to which you can generalize." Strong similarities suggest "broad applicability."
The work is supported by the National Institutes of Health (National Institute of General Medical Sciences and National Institute of Mental Health) and the National Science Foundation.
Journal
Science