Circadian regulation of macromolecular complex turnover and proteome renewal.

Although costly to maintain, protein homeostasis is indispensable for normal cellular function and long-term health. In mammalian cells and tissues, daily variation in global protein synthesis has been observed, but its utility and consequences for proteome integrity are not fully understood. Using several different pulse-labelling strategies, here we gain direct insight into the relationship between protein synthesis and abundance proteome-wide. We show that protein degradation varies in-phase with protein synthesis, facilitating rhythms in turnover rather than abundance. This results in daily consolidation of proteome renewal whilst minimising changes in composition. Coupled rhythms in synthesis and turnover are especially salient to the assembly of macromolecular protein complexes, particularly the ribosome, the most abundant species of complex in the cell. Daily turnover and proteasomal degradation rhythms render cells and mice more sensitive to proteotoxic stress at specific times of day, potentially contributing to daily rhythms in the efficacy of proteasomal inhibitors against cancer. Our findings suggest that circadian rhythms function to minimise the bioenergetic cost of protein homeostasis through temporal consolidation of protein turnover.

Non-transcriptional processes in circadian rhythm generation.

'Biological clocks' orchestrate mammalian biology to a daily rhythm. Whilst 'clock gene' transcriptional circuits impart rhythmic regulation to myriad cellular systems, our picture of the biochemical mechanisms that determine their circadian (∼24 hour) period is incomplete. Here we consider the evidence supporting different models for circadian rhythm generation in mammalian cells in light of evolutionary factors. We find it plausible that the circadian timekeeping mechanism in mammalian cells is primarily protein-based, signalling biological timing information to the nucleus by the post-translational regulation of transcription factor activity, with transcriptional feedback imparting robustness to the oscillation via hysteresis. We conclude by suggesting experiments that might distinguish this model from competing paradigms.