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.
Highlights
Periodic oscillations are essential for biological phenomena such as cell cycle regulation and circadian rhythms [1,2]
We demonstrate that DNA target sites can be employed as a powerful design parameter to finely tune and control the dynamic behavior of a biomolecular circuit, the activator-repressor clock of Figure 1a in particular
In the models surveyed in the literature, the fundamental mechanism responsible for this oscillatory behavior is well captured by a reduced twodimensional model that describes the rate of change of the activator and repressor concentrations. This model is obtained by taking into account that the period of oscillations occurs in a timescale slower than the dynamics of multimerization, binding and dissociation interactions, so that quasi-steady state approximations can be made [6,9,20]
Summary
Periodic oscillations are essential for biological phenomena such as cell cycle regulation and circadian rhythms [1,2]. Several studies attribute these oscillations to bio-molecular clocks composed of genes arranged in feedback networks [3,4]. The repressor module, in turn, represses the activator (Figure 1a). This motif has been shown to be remarkably robust to biological noise [5], leading to synthetic implementations as model systems to study natural clocks [6,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
