Post-translational modifications in circadian rhythms

Abstract

The pace has quickened in circadian biology research. In particular, an abundance of results focused on post-translational modifications (PTMs) is sharpening our view of circadian molecular clockworks. PTMs affect nearly all aspects of clock biology; in some cases they are essential for clock function and in others, they provide layers of regulatory fine-tuning. Our goal is to review recent advances in clock PTMs, help make sense of emerging themes, and spotlight intriguing (and perhaps controversial) new findings. We focus on PTMs affecting the core functions of eukaryotic clocks, in particular the functionally related oscillators in Neurospora crassa, Drosophila melanogaster, and mammalian cells.

Figure 1. Circadian clocks from organism to mechanism

Over the last several decades our picture of circadian clocks has spiraled out from a physiological description of clock-controlled activities at the organismal level, through an understanding of clocks as being bound within single cells, to revealing a molecular mechanism that is predominantly constrained within the interplay between positive (+TF) and negative (−F) forces. A clearer picture of the clockworks of these systems is beginning to emerge, showing that many of the processes and components are controlled through post-translational modification.

Figure 2_[SC1]. Vignettes of circadian post-translational modifications

A number of clock PTMs are depicted in a simplified series of cartoons. Representative PTMs are shown and do not reflect the action in all species. For more detail, refer to the text. a) PAS-domain containing positively acting transcription factors (+TFs, green boxes) shuttle (bi-directional arrow) between the nucleus_[SC2] on DNA and cytoplasm. b) DNA-bound +TFs activate transcription (bent arrow) of negatively acting factors (−Fs, red ovals). c) Kinases (blue circles) and phosphatases (orange circles) compete to establish a pattern of progressive phosphorylation (P) which can have multiple consequences including cytoplasmic retention of −Fs. d) −Fs transport kinases, which along with independent kinases (blue oval) phosphorylate (curved arrows) +TFs (and/or −Fs) via transient interactions (bi-directional arrow) leading to inactivation of +TFs and export from the nucleus (arrow). e) A mammalian +TF can act as a histone acetyltransferase (curved arrow, Ac; acetyl group) to inactivate its partner. f) In mammals, a deacetylase can remove inhibitory Ac from +TFs and −Fs. g) In mammals, +TFs can be sumoylated (Su) leading to their ubiquitylation (Ub) and degradation. h) Progressive phosphorylation (Ps) on −Fs leads to F-box binding (yellow box), ubiquitylation (Ub) and subsequent degradation. i) In Neurospora mature −F can promote +TF complex formation. j) Upon DNA damage (XXX), DNA-damage dependent kinases (blue hexagon) can phosphorylate −Fs accelerating their degradation. k) Multiple outcomes of −F degradation are depicted. Clusters of phosphosites can mediate different consequences including stabilization, potentiation of −F efficacy and degradation.