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.
journal_name
Proc Natl Acad Sci U S Aauthors
Beesley S,Kim DW,D'Alessandro M,Jin Y,Lee K,Joo H,Young Y,Tomko RJ Jr,Faulkner J,Gamsby J,Kim JK,Lee Cdoi
10.1073/pnas.2003524117subject
Has Abstractpub_date
2020-11-10 00:00:00pages
28402-28411issue
45eissn
0027-8424issn
1091-6490pii
2003524117journal_volume
117pub_type
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