The Ups and Downs of Biological Timers Michael Kovshilovsky SoCalBSI 2005

Background Cell cycle progression and cell differentiation are crucial processes Cell cycle progression and cell differentiation are crucial processes The need to perform a series of events in a systematic and timely manner is fundamental to many biological processes The need to perform a series of events in a systematic and timely manner is fundamental to many biological processes In certain systems the delay times between events are controlled by the interacting proteins that propagate the systems In certain systems the delay times between events are controlled by the interacting proteins that propagate the systems

Background Protein levels inside cells can encounter genetic and environmental alterations Protein levels inside cells can encounter genetic and environmental alterations These environmental fluctuations affect protein levels and their interactions These environmental fluctuations affect protein levels and their interactions Question: How is reliable timing maintained? Question: How is reliable timing maintained?

Mechanisms Mechanisms have evolved that buffer biological processes against these fluctuations Mechanisms have evolved that buffer biological processes against these fluctuations Sustaining a series of events may seem simple when completion of one event directly triggers the next, but this is not always the case Sustaining a series of events may seem simple when completion of one event directly triggers the next, but this is not always the case Often times ordered events are produced by a self- sustained network, which functions even in the absence of feedback signals Often times ordered events are produced by a self- sustained network, which functions even in the absence of feedback signals This suggests that not only is order important, but the timing of the events is as well. This suggests that not only is order important, but the timing of the events is as well.

Focus of Paper This research paper studies whether mechanisms that code for delay times can also buffer those times against fluctuations in gene dosage

Coding for delay times Strategy 1-Accumulation Accumulation of a protein can occur by enhancing the production, or inhibiting its degradation Accumulation of a protein can occur by enhancing the production, or inhibiting its degradation As the amount of protein passes a certain threshold a sequence of events will follow As the amount of protein passes a certain threshold a sequence of events will follow Strategy 2-Degradation Once the protein has decayed below a certain threshold level a sequence of events occurs In essence, accumulation times are the same as degradation times.

Sensitivity of delay time Sensitivity of the delay times in respect to fluctuations in the production and decay rate of the protein were also examined Sensitivity of the delay times in respect to fluctuations in the production and decay rate of the protein were also examined The sensitivity of the delay time is defined by the relative change in the delay time The sensitivity of the delay time is defined by the relative change in the delay time

Sensitivity of delay time Delay times encoded by decay show a lower sensitivity than delay times encoded by accumulation Delay times encoded by decay show a lower sensitivity than delay times encoded by accumulation

Degradation When fluctuations in the degradation rate increase, different buffering mechanisms will need to be employed When fluctuations in the degradation rate increase, different buffering mechanisms will need to be employed One such mechanism that could reduce fluctuations relies on in-cis degradation, where each molecule promotes its own degradation One such mechanism that could reduce fluctuations relies on in-cis degradation, where each molecule promotes its own degradation

In-cis degradation This type of mechanism has been found in cell-cycle timing This type of mechanism has been found in cell-cycle timing Example: Example: –UbcH10 undergoes in-cis degradation so it can start S-phase

Non-linear degradation Enhances robustness Enhances robustness Feedback that enhances degradation at early times, while maintaining moderate decay during the rest of the time Feedback that enhances degradation at early times, while maintaining moderate decay during the rest of the time Example: Example: –Degrading protein enhances its own decay, either directly or by changing activity of a third protein

Non-linear degradation Enables flexible degradation rates Enables flexible degradation rates Non-linear degradation is less sensitive than linear degradation Non-linear degradation is less sensitive than linear degradation

Conclusion Self-enhanced degradation processes will be favored in processes where maintaining the robustness of timing is important Self-enhanced degradation processes will be favored in processes where maintaining the robustness of timing is important Ensuring this timing may particularly important in order to support feedback among several processes that are occurring in parallel Ensuring this timing may particularly important in order to support feedback among several processes that are occurring in parallel