CRYPTOCHROMES.pdf (1.41 MB)
Download file

CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping

Download (1.41 MB)
journal contribution
posted on 18.06.2021, 11:02 by Marrit Putker, David CS Wong, Estere Seinkmane, Nina M Rzechorzek, Aiwei Zeng, Nathaniel P Hoyle, Johanna E Chesham, Mathew D Edwards, Kevin A Feeney, Robin Fischer, Nicolai Peschel, Ko-Fan Chen, Michael Vanden Oever, Rachel S Edgar, Christopher P Selby, Aziz Sancar, John S O'Neill
Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRY-deficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRY-less oscillations are variable in their expression and have shorter periods than wild-type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1δ/ε activity to be maintained. In the absence of CRY-mediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post-translational.

Funding

MP was supported by the Dutch Cancer Foundation (KWF, BUIT-2014-6637) and EMBO (ALTF-654-2014). JON was supported by the Medical Research Council (MC_UP_1201/4) and the Wellcome Trust (093734/Z/10/Z). NP and RF were supported by the Deutsche Forschungsgemeinschaft FKZ (Pe1798/2-1). AS and CPS were supported by the National Institutes of Health (GM118102). NMR was supported by the Medical Research Council (MR/S022023/1).

History

Citation

EMBO J (2021)40:e106745

Author affiliation

Department of Genetics and Genome Biology

Version

VoR (Version of Record)

Published in

The EMBO Journal

Volume

40

Publisher

EMBO Press

issn

0261-4189

eissn

1460-2075

Acceptance date

18/12/2020

Copyright date

2021

Available date

18/06/2021

Spatial coverage

England

Language

English