A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints

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dc.contributor.authorZou, Xianlinen
dc.contributor.authorKim, Dae Wooken
dc.contributor.authorGotoh, Tetsuyaen
dc.contributor.authorLiu, Jingjingen
dc.contributor.authorKim, Jae Kyoungen
dc.contributor.authorFinkielstein, Carla V.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2020-08-06T17:58:34Zen
dc.date.available2020-08-06T17:58:34Zen
dc.date.issued2020-04-16en
dc.description.abstractCircadian rhythms form a self-sustaining, endogenous, time-keeping system that allows organisms to anticipate daily environmental changes. The core of the clock network consists of interlocking transcriptional-translational feedback loops that ensures that metabolic, behavioral, and physiological processes run on a 24 h timescale. The hierarchical nature of the clock manifests itself in multiple points of control on the daily cell division cycle, which relies on synthesis, degradation, and post-translational modification for progression. This relationship is particularly important for understanding the role of clock components in sensing stress conditions and triggering checkpoint signals that stop cell cycle progression. A case in point is the interplay among the circadian factor PERIOD2 (PER2), the tumor suppressor p53, and the oncogenic mouse double minute-2 homolog protein (MDM2), which is the p53’s negative regulator. Under unstressed conditions, PER2 and p53 form a stable complex in the cytosol and, along with MDM2, a trimeric complex in the nucleus. Association of PER2 to the C-terminus end of p53 prevents MDM2-mediated ubiquitylation and degradation of p53 as well as p53’s transcriptional activation. Remarkably, when not bound to p53, PER2 acts as substrate for the E3-ligase activity of MDM2; thus, PER2 is degraded in a phosphorylation-independent fashion. Unexpectedly, the phase relationship between PER2 and p53 are opposite; however, a systematic modeling approach, inferred from the oscillatory time course data of PER2 and p53, aided in identifying additional regulatory scenarios that explained, a priori, seemingly conflicting experimental data. Therefore, we advocate for a combined experimental/mathematical approach to elucidating multilevel regulatory cellular processes.en
dc.description.sponsorshipThis work was supported by the National Science Foundation MCB division (MCB-1517298) to CF, VT Open Access Subvention Fund, and Human Frontiers Science Program Organization (RGY0063/2017), National Research Foundation of Korea Grant (NRF-2016 RICIB 3008468) to JK, and NRF- 2017-Fostering Core Leaders of the Future Basic Science Program/Global Ph.D. Fellowship Program to DK.en
dc.format.extent9 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationZou X, Kim DW, Gotoh T, Liu J, Kim JK and Finkielstein CV (2020) A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints. Front. Physiol. 11:327. doi: 10.3389/fphys.2020.00327en
dc.identifier.doihttps://doi.org/10.3389/fphys.2020.00327en
dc.identifier.urihttp://hdl.handle.net/10919/99572en
dc.identifier.volume11en
dc.language.isoenen
dc.publisherFrontiers Mediaen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectcircadian rhythmsen
dc.subjecttumor suppressoren
dc.subjectcheckpoint signalingen
dc.subjectclock genesen
dc.subjectp53en
dc.subjectmathematical modelingen
dc.subjectsystematic approachen
dc.titleA Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpointsen
dc.title.serialFrontiers in Psychologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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