Optimal regulation of protein degradation to schedule cellular events with precision

Abstract: An important occurrence in many cellular contexts is the crossing of a prescribed threshold by a regulatory protein. The timing of such events is stochastic as a consequence of the innate randomness in gene expression. A question of interest is to understand how gene expression is regulated to achieve precision in event timing. To address this, we model event timing using the first-passage time framework - a mathe- matical tool to analyze the time when a stochastic process first crosses a specific threshold. The protein evolution is described via a simple stochastic model of gene expression. Moreover, we consider the feedback regulation of protein degradation to be a possible noise control mechanism employed to achieve the precision. Exact analytical formulas are developed for the distribution and moments of the first-passage time. Using these expressions, we investigate for the optimal feedback strategy such that noise (coefficient of variation squared) in event timing is minimized around a given fixed mean time. Our results show that the minimum noise is achieved when the protein degradation rate is zero for all protein levels. Lastly, the implications of this finding are discussed.