Figure 1.

Models for circadian rhythm generation.

(a) Biological clocks consist of a timekeeping mechanism whose phase, period and amplitude may be regulated by various inputs. Outputs of the clock control rhythmic metabolism, physiology and behaviour of organisms, and some of these may in turn feedback to modulate the timekeeping mechanism itself, thus also acting as inputs. Rhythmic input regulation is not essential for circadian rhythm generation however. (b) TTFL-based model for cellular circadian timekeeping: the TTFL itself can sustain oscillations, with the 24-hour period conferred by a post-translational delay-timer. The clock-controlled genes are direct outputs of the TTFL, and result in rhythmic cell function. Some of these outputs can feed back to regulate TTFL function. (c) Post-translational model for cellular circadian timekeeping: a self-sustained post-translational timekeeping mechanism is sufficient to sustain ∼24h rhythms in enzyme activity. The TTFL acts as a signal transducer, receiving timing information from this biochemical oscillation through post-translational modification of TTFL components, to differentially regulate transcription of clock and clock-controlled genes. The TTFL may confer robustness upon the post-translational oscillation by amplifying timing information and also by differentially regulating the activity of the enzymes that post-translationally modify clock proteins.