By means of endogenous circadian (approx. 24 hr) """"""""clocks"""""""" or pacemakers that can be synchronized to the daily and seasonal changes in external time cues, most notably visible light and ambient temperature, life forms anticipate environmental transitions, perform activities at biologically advantageous times during the day and undergo characteristic seasonal responses. Core features of many, if not all, circadian clocks are transcriptional feedback loops that generate daily cycles in the levels of clock mRNAs. However, posttranslational mechanisms make significant contributions to the temporal regulation of clock protein levels and activities. Time-of-day specific differences in phosphorylation that result in phase-specific changes in protein stability appear to be a common strategy in generating daily cycles in clock protein abundance. The main goal of this proposal is to better understand the role of clock protein phosphorylation in circadian function using Drosophila as an animal model system. In particular, a conserved feature of animal clocks is that PERIOD (PER) proteins undergo daily rhythms in phosphorylation that are essential for the normal progression of the time-keeping mechanism. Indeed, it is likely that the """"""""ticking"""""""" of animal clocks is based on daily changes in the phosphorylated status of PER proteins. However, it is not clear what roles different phosphorylation sites play in regulating PER levels and activity. In this proposal, phosphorylation sites on the Drosophila PER protein will be identified and their specific contributions to the underlying clock mechanism determined. Understanding how phosphorylation regulates PER metabolism and activity has potential health implications as evidenced from the fact that mutations altering the phosphorylation of human PER2 or a key kinase that phosphorylates PER proteins (called CKI4) are linked to several familial sleep disorders. Moreover, recent findings in cyanobacteria suggest that the most basic and ancient building block of circadian clocks is a biochemical oscillator based on time-of-day specific phosphorylation of one or more key clock proteins. Thus, our studies should reveal novel insights on the biochemical basis for circadian clocks, which could lead to better treatments for disorders associated with clock dysfunction in humans.

Public Health Relevance

Humans exhibit daily changes in physiology and behavior, such as our wake-sleep cycles, that are controlled by a network of specialized cells called circadian clocks. A key gear in the timing mechanism of these cellular clocks is a protein called PERIOD that when mutated can lead to severe sleep disorders and other health related problems. This proposal will investigate how PER proteins contribute to the """"""""ticking"""""""" of the clock.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034958-15
Application #
7754658
Study Section
Special Emphasis Panel (ZRG1-NCF-D (09))
Program Officer
Mitler, Merrill
Project Start
1995-07-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
15
Fiscal Year
2010
Total Cost
$329,302
Indirect Cost
Name
Rutgers University
Department
Type
Schools of Medicine
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Kwok, Rosanna S; Li, Ying H; Lei, Anna J et al. (2015) The Catalytic and Non-catalytic Functions of the Brahma Chromatin-Remodeling Protein Collaborate to Fine-Tune Circadian Transcription in Drosophila. PLoS Genet 11:e1005307
Yildirim, Evrim; Chiu, Joanna C; Edery, Isaac (2015) Identification of Light-Sensitive Phosphorylation Sites on PERIOD That Regulate the Pace of Circadian Rhythms in Drosophila. Mol Cell Biol 36:855-70
Lee, Euna; Jeong, Eun Hee; Jeong, Hyun-Jeong et al. (2014) Phosphorylation of a central clock transcription factor is required for thermal but not photic entrainment. PLoS Genet 10:e1004545
Mahesh, Guruswamy; Jeong, EunHee; Ng, Fanny S et al. (2014) Phosphorylation of the transcription activator CLOCK regulates progression through a ? 24-h feedback loop to influence the circadian period in Drosophila. J Biol Chem 289:19681-93
Kim, Eun Young; Jeong, Eun Hee; Park, Sujin et al. (2012) A role for O-GlcNAcylation in setting circadian clock speed. Genes Dev 26:490-502
Edery, Isaac (2011) A master CLOCK hard at work brings rhythm to the transcriptome. Genes Dev 25:2321-6
Chiu, Joanna C; Ko, Hyuk Wan; Edery, Isaac (2011) NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed. Cell 145:357-70
Edery, Isaac (2011) A morning-induced, phosphorylation-gated repressor times evening gene expression: a new way for circadian clocks to use an old trick. Mol Cell 44:679-81
Ko, Hyuk Wan; Kim, Eun Young; Chiu, Joanna et al. (2010) A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3beta/SGG in circadian clocks. J Neurosci 30:12664-75
Sun, Woo Chul; Jeong, Eun Hee; Jeong, Hyun-Jeong et al. (2010) Two distinct modes of PERIOD recruitment onto dCLOCK reveal a novel role for TIMELESS in circadian transcription. J Neurosci 30:14458-69

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