The Biochemical Basis of Circadian Synchronisation

Circadian rhythms align almost every aspect of mammalian biology with the external day-night cycle. To achieve this successfully, the timing of circadian rhythms must be synchronised with specific external events, particularly when we see light or eat food. Mistiming of these events and the resulting disruption of circadian rhythms is associated with increased disease risk. Mammalian circadian rhythms are controlled by the transcription factor CLOCK:BMAL1 and its regulators PERIOD, CRY and CK1, which form a series of macromolecular complexes over the 24h circadian cycle to drive rhythms in transcription. How synchronising cues, like light and food, input into this protein machinery to synchronise it to a specific time of day is currently poorly understood at the molecular level. I propose to elucidate how circadian synchronisation is achieved by the proteins of the circadian clockwork (Aim 1) and how post-translational modification of these proteins following different synchronising cues regulates synchronisation timing (Aim 2). Using biophysical, structural and cell biology approaches, in combination with a novel cellular model for circadian disruption, we will then investigate how mistiming of circadian synchronising events reduces cellular function and promotes disease (Aim 3).