The dysregulation of the circadian cycle significantly contributes to cancer and metabolic disorders;utilizing biochemistry we hope to unveil the molecular mechanism behind this complex process. Specifically, PERIOD2 (hPER2), a key clock component responsible for the regulation of circadian genes has been implicated in tumor suppression. Mammalian Per2 is regulated by reversible phosphorylation modulating both protein and RNA levels, thus regulating downstream circadian genes and circadian period. Yet the mechanism, and specific enzymes involved in Per2 phosphorylation are largely unknown. The objective of this work is to understand the mechanism and role of PER2 phosphorylation in circadian cycle regulation. Since the biochemical mechanism of PER2 regulation is largely unknown, we hypothesize that PER2 is regulated by a specific set or single kinase and specific differential phosphorylation will affect the circadian cycle PER2.
In Aim 1 we outline the details of the adaptation and development of new biochemical and genetic methodologies to identify key kinase regulators of Per2 during the circadian cycle.
In Aim 2 we will also characterize phosphorylation of Per2 in the CKI domain by utilizing a novel mutation to Ser665 to better understand the specific function of differential phosphorylation effects on the circadian cycle.
The dysregulation of the circadian cycle significantly contributes to cancer and metabolic disorders;our research aims to elucidate the biological mechanism behind the complex process of post translational regulation of the circadian cycle. Our hope is that, as has proved the case for many other diseases, understanding the basic mechanisms of regulation will give insight into the mechanisms of disease during dysfunction.
|Hallows, William C; Ptacek, Louis J; Fu, Ying-Hui (2013) Solving the mystery of human sleep schedules one mutation at a time. Crit Rev Biochem Mol Biol 48:465-75|