Genes That Keep Clocks Ticking

Fruit flies, like people, follow a daily schedule of eating, resting, and other activities. Now neurogeneticists have discovered two genes that appear to be long-sought missing pieces in the biological clocks that regulate these activities. These new fruit fly genes, reported in tomorrow's Cell, are remarkably similar to genes found in mice and people--indicating that all these organisms depend on the same molecular mechanisms to keep time.

Clock biologists think that two proteins--per and tim--keep the circadian beat by inhibiting their own genes. Over the course of the day, the amount of these proteins increases and gradually turns off the genes. The proteins then break down over time, freeing up the genes to be active again and start the cycle anew. But researchers knew they were missing a key piece of the mechanism because neither the per nor tim protein binds DNA directly--which would be required to turn genes off.

To search for other timekeeping genes, Jeffrey Hall, Michael Rosbash and other scientists at Brandeis University in Waltham, Massachusetts, first randomly mutated fruit fly genes with toxic chemicals. The team then looked for offspring with altered or missing circadian rhythms. Some of these mutants had defective per and tim genes, but the researchers also discovered two new timekeeping genes, which they named dclock and cyc. Fruit flies with two defective copies of either gene showed no rhythmic behaviors, while those with a mutation in one copy of either gene didn't follow a 24-hour schedule.

Both the dclock and cyc proteins have a section that binds to DNA and another section that enables them to link up with certain proteins, the researchers say. This suggests, says geneticist Charalambos Kyriacou from the University of Leicester, United Kingdom, that per and tim may latch on to dclock and cyc, thereby gaining a way to influence genes. And other researchers have shown that the mammalian version of these two proteins pair up and can attach to DNA near the per gene, activating it. "It's brilliant work," says Kyriacou.