9421475 Organisms as diverse as fungi, flies, and humans exhibit circadian rhythms, daily rhythms in physiology and behavior that are generated and coordinated by an internal timekeeping system, referred to as a 'circadian clock'. Circadian clocks in virtually all organisms examined to date share certain fundamental properties. These include an intrinsic rhythm that is slightly different than the natural 24-hour day, the exact value depending on the species, the ability to synchronize to the natural day by exposure to light-dark cycles, and a highly-regular rhythmicity that does not change in rate at different temperatures, unlike simple chemical reactions. The genetic and biochemical basis of the circadian clock is only poorly understood, despite its importance in organizing physiology and behavior in humans and other organisms. The most sophisticated information to date has been obtained from genetic studies in the fruitfly Drosophila melanogaster, which have led to the cloning and characterization of a circadian clock gene called period. Recent genetic and biochemical experiments have confirmed that the protein product of the period gene is a key component of the circadian clock. Accumulating evidence suggests that the 'works' of the clock consist of a precisely-timed oscillation in the abundance of the period protein. This molecular rhythm results from a highly-regulated rhythmic synthesis of the period protein, a process in which the period protein itself and at least several as-yet uncharacterized proteins are involved. The objective of these investigations is to identify novel proteins that play a role in the genesis or regulation of circadian oscillations. The strategy being employed is to identify the as-yet uncharacterized proteins that interact with the period protein and which are involved in regulating its biological activity. The long-range goal is to understand quantitatively how a small set of genes and their protein products can form a precise, self-sustaining d aily timing mechanism.