The ups and downs of biological timers

BACKGROUND: The need to execute a sequence of events in an orderly and timely manner is central to many biological processes, including cell cycle progression and cell differentiation. For self-perpetuating systems, such as the cell cycle oscillator, delay times between events are defined by the network of interacting proteins that propagates the system. However, protein levels inside cells are subject to genetic and environmental fluctuations, raising the question of how reliable timing is maintained. RESULTS: We compared the robustness of different mechanisms for encoding delay times to fluctuations in protein expression levels. Gradual accumulation and gradual decay of a regulatory protein have an equivalent capacity for defining delay times. Yet, we find that the former is highly sensitive to fluctuations in gene dosage, while the latter can buffer such perturbations. In particular, a positive feedback where the degrading protein auto-enhances its own degradation may render delay times practically insensitive to gene dosage. CONCLUSION: While our understanding of biological timing mechanisms is still rudimentary, it is clear that there is an ample use of degradation as well as self-enhanced degradation in processes such as cell cycle and circadian clocks. We propose that degradation processes, and specifically self-enhanced degradation, will be preferred in processes where maintaining the robustness of timing is important.