Analysis of clock proteins in their non-circadian roles

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Circadian clocks are evolutionary conserved coordinators of behavioral and physiological processes. Malfunctions of circadian clocks in humans lead to serious pathologies such as sleep disorders and cancer. Circadian timekeeping is accomplished by molecular feedback loops that involve several clock genes and their proteins. The role of two genes period(per)and timeless(tim) has been well established in the clock feedback loop, which operates in the model organism Drosophila melanogaster. The products of these two genes, proteins PER and TIM,translocate to cell nuclei and are subsequently degraded; both events are essential for clock function. Surprisingly, in the ovary, these proteins behave differently. Their levels do not cycle; instead, they remain stable and cytoplasmic at all times. We have evidence that non-circadian expression of PER and TIM in the ovary may have important functions in the modulation of egg production. We hypothesize that clock genes may be interacting with components of signaling pathways that govern metabolic homeostasis and nutrient allocation. We propose to use biochemical and genetic tools to test this hypothesis in two specific aims. First, we will study genetic and biochemical interactions of PER and TIM in the ovary and test their functional significance using fecundity related phenotypes. Second, we will perform protein interaction screens to identify novel proteins that may interact with cytoplasmic PER and TIM. Results obtained in this study will give us important insights into the functional significance of non-circadian expression of clock proteins. There is increasing evidence that genes that were thought to act exclusively as clock components have other important pleiotropic roles. They act in a non-circadian manner in both fly and mammals. Therefore, understanding the non-circadian functions of clock genes in a model organism should provide valuable insights into similar processes related to human health.