Analysis of clock proteins in their non-circadian roles

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DESCRIPTION (provided by applicant): 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. Despite such unorthodox behavior, ovarian PER and TIM have important functions in the modulation of egg production. We hypothesize that PER and TIM may undergo different post-translational modifications in the ovary than they do in the clock cells. We propose to use biochemical and genetic tools to test this hypothesis in three specific aims. First, we will study interactions of PER and TIM in the ovary and their functional significance. Second, we will investigate posttranslational modifications of PER and TIM related to phosphorylation. Finally, we will explore the reasons for the lack of TIM degradation in response to light in the ovary. Results obtained in this study will give us important insights into the functional significance of non-circadian expression of clock proteins in the fly ovary. 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 Drosophila and mammals. Therefore, understanding the non-circadian functions of clock genes in a model organism should provide valuable insights into human health.