title: Tuning genetic clocks employing DNA binding sites.
abstract: Periodic oscillations play a key role in cell physiology from the cell cycle to circadian clocks. The interplay of positive and negative feedback loops among genes and proteins is ubiquitous in these networks. Often, delays in a negative feedback loop and/or degradation rates are a crucial mechanism to obtain sustained oscillations. How does nature control delays and kinetic rates in feedback networks? Known mechanisms include proper selection of the number of steps composing a feedback loop and alteration of protease activity, respectively. Here, we show that a remarkably simple means to control both delays and effective kinetic rates is the employment of DNA binding sites. We illustrate this design principle on a widely studied activator-repressor clock motif, which is ubiquitous in natural systems. By suitably employing DNA target sites for the activator and/or the repressor, one can switch the clock "on" and "off" and precisely tune its period to a desired value. Our study reveals a design principle to engineer dynamic behavior in biomolecular networks, which may be largely exploited by natural systems and employed for the rational design of synthetic circuits.
authors.affiliation: Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan, United States of America. ddv@mit.edu
authors.forename: Shridhar
authors.initials: S
authors.lastname: Jayanthi
authors.forename: Domitilla
authors.initials: D
authors.lastname: Del Vecchio
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D001683:Biological Clocks; D003198:Computer Simulation; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000502:physiology; D037941:Silencer Elements, Transcriptional; D015534:Trans-Activators / Q000502:physiology
chemical_list: D012097:Repressor Proteins; D015534:Trans-Activators