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NONO couples the circadian clock to the cell cycle.

ABSTRACT: Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.

SUBMITTER: Kowalska E

PROVIDER: S-EPMC3562797 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

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NONO couples the circadian clock to the cell cycle.

Kowalska Elzbieta E Ripperger Juergen A JA Hoegger Dominik C DC Bruegger Pascal P Buch Thorsten T Birchler Thomas T Mueller Anke A Albrecht Urs U Contaldo Claudio C Brown Steven A SA

Proceedings of the National Academy of Sciences of the United States of America 20121224 5

Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately norm ...[more]

PMID: 23267082

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Project description:The cell cycle and the circadian clock represent major cellular rhythms, which appear to be coupled. Thus the circadian factor BMAL1 controls the level of cell cycle proteins such as Cyclin E and WEE1, the latter of which inhibits the kinase CDK1 that governs the G2/M transition. In reverse the cell cycle impinges on the circadian clock through direct control by CDK1 of REV-ERB?, which negatively regulates BMAL1. These observations provide evidence for bidirectional coupling of the cell cycle and the circadian clock. By merging detailed models for the two networks in mammalian cells, we previously showed that unidirectional coupling to the circadian clock can entrain the cell cycle to 24 or 48 h, depending on the cell cycle autonomous period, while complex oscillations occur when entrainment fails. Here we show that the reverse unidirectional coupling via phosphorylation of REV-ERB? or via mitotic inhibition of transcription, both controlled by CDK1, can elicit entrainment of the circadian clock by the cell cycle. We then determine the effect of bidirectional coupling of the cell cycle and circadian clock as a function of their relative coupling strengths. In contrast to unidirectional coupling, bidirectional coupling markedly reduces the likelihood of complex oscillations. While the two rhythms oscillate independently as long as both couplings are weak, one rhythm entrains the other if one of the couplings dominates. If the couplings in both directions become stronger and of comparable magnitude, the two rhythms synchronize, generally at an intermediate period within the range defined by the two autonomous periods prior to coupling. More surprisingly, synchronization may also occur at a period slightly below or above this range, while in some conditions the synchronization period can even be much longer. Two or even three modes of synchronization may sometimes coexist, yielding examples of birhythmicity or trirhythmicity. Because synchronization readily occurs in the form of simple periodic oscillations over a wide range of coupling strengths and in the presence of multiple connections between the two oscillatory networks, the results indicate that bidirectional coupling favours the robust synchronization of the cell cycle and the circadian clock.

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NONO couples the circadian clock to the cell cycle.

Publications

NONO couples the circadian clock to the cell cycle.

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