Genetic and Molecular Dissection of the Neurospora Clock

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 DESCRIPTION (provided by applicant): Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization known as a circadian rhythm. The cellular machinery responsible for generating rhythms is collectively known as the biological clock. A healthy circadian clock underlies both physical and mental health. Because of the ubiquity of its influence on human mental and physiological processes - from circadian changes in basic human physiology to the clear involvement of rhythms in work/rest cycles and sleep - understanding the clock is basic to prevention and treatment of many physical and mental illnesses, from metabolic disorders to sleep/wake dysfunction and cancer. Our research has used genetic and molecular studies of the model eukaryote Neurospora to further our understanding of the organization of the circadian oscillator. Planned research lies within four foci. Focus #1 builds upon our understanding of the interplay between structure and function in core clock components. New data are inconsistent with some existing models and predicted roles for clock proteins. We will identify updated roles, interactions, and structures, as well as probing how clock-controlled phosphorylation guides essential interactions and activities of clock components. Focus #2 is centered on a deeper look at the role of phosphorylation in temperature compensation and the kinases that bring this about. Focus #3 builds upon our strong grounding in genetics and genomics as well as ongoing work that has identified three novel genes whose mutation alters period length by as much 18 hours. Examination of the bases of these effects will take us into aspects metabolism and gene expression heretofore unexplored in terms of circadian biology. Focus #4 explores completely new territory, pioneering the use of cell biological tools to complement genetics, exploring the regulatory plasticity of architecture of the circadian oscillator, and as time allows probing a novel genetic system that generates a circadian rhythm despite the absence of canonical clock components. Our long term goals are to describe, in the language of genetics and biochemistry, the feedback cycle comprising the circadian clock, how this cycle is synchronized with the environment, and how time information generated by the feedback cycle is used to regulate the behavior of cells and organisms. These projects are complementary and mutually enriching in that they rely on genetic and molecular techniques to dissect, and ultimately to understand, the organization of cells as a function of time.