한빛사 논문
Stephen Beesleya,1, Dae Wook Kimb,1, Matthew D’Alessandroa,2, Yuanhu Jina, Kwangjun Leea, Hyunjeong Jooa,c, Yang Youngc, Robert J. Tomko Jra, John Faulknerd, Joshua Gamsbyd, Jae Kyoung Kimb,3, and Choogon Leea,3
aDepartment of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306; bDepartment of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; cDepartment of Systems Biology, Sookmyung Women’s University, Seoul 04310, Republic of Korea; and dDepartment of Molecular Medicine, University of South Florida, Tampa, FL 33620
1S.B. and D.W.K. contributed equally to this work.
2Present address: School of Physical Therapy, Florida Southern College, Lakeland, FL 33801.
3To whom correspondence may be addressed.
Abstract
The circadian clock is based on a transcriptional feedback loop with an essential time delay before feedback inhibition. Previous work has shown that PERIOD (PER) proteins generate circadian time cues through rhythmic nuclear accumulation of the inhibitor complex and subsequent interaction with the activator complex in the feedback loop. Although this temporal manifestation of the feedback inhibition is the direct consequence of PER’s cytoplasmic trafficking before nuclear entry, how this spatial regulation of the pacemaker affects circadian timing has been largely unexplored. Here we show that circadian rhythms, including wake-sleep cycles, are lengthened and severely unstable if the cytoplasmic trafficking of PER is disrupted by any disease condition that leads to increased congestion in the cytoplasm. Furthermore, we found that the time delay and robustness in the circadian clock are seamlessly generated by delayed and collective phosphorylation of PER molecules, followed by synchronous nuclear entry. These results provide clear mechanistic insight into why circadian and sleep disorders arise in such clinical conditions as metabolic and neurodegenerative diseases and aging, in which the cytoplasm is congested.
circadian rhythm, PERIOD, negative feedback loop, cytoplasmic trafficking, bistable phospho-switch
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TOP52020년 후보
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