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Abstract
We study a theoretical model for the toxin-antitoxin (hok/sok) mechanism for plasmid maintenance in bacteria. Toxin-antitoxin systems enforce the maintenance of a plasmid through post-segregational killing of cells that have lost the plasmid. Key to their function is the tight regulation of expression of a protein toxin by an sRNA antitoxin. Here, we focus on the nonlinear nature of the regulatory circuit dynamics of the toxin-antitoxin mechanism. The mechanism relies on a transient increase in protein concentration rather than on the steady state of the genetic circuit. Through a systematic analysis of the parameter dependence of this transient increase, we confirm some known design features of this system and identify new ones: for an efficient toxin-antitoxin mechanism, the synthesis rate of the toxin’s mRNA template should be lower that of the sRNA antitoxin, the mRNA template should be more stable than the sRNA antitoxin, and the mRNA-sRNA complex should be more stable than the sRNA antitoxin. Moreover, a short half-life of the protein toxin is also beneficial to the function of the toxin-antitoxin system. In addition, we study a therapeutic scenario in which a competitor mRNA is introduced to sequester the sRNA antitoxin, causing the toxic protein to be expressed.
Highlights
IntroductionSmall regulatory RNA (sRNA) plays an important role in gene regulation in organisms from bacteria to mammals by controlling for example translation and/or mRNA stability and the list of known RNA regulation systems keeps increasing at a rapid pace [1,2,3]. sRNA regulation possesses characteristics that are distinct from protein regulation, in particular a threshold-linear response, which provides an ultrasensitive mechanism for regulatory switching, and the possibility of hierarchical crosstalk, which allows prioritizing of expression [4].Some of the best known sRNA regulation systems are related to plasmid replication and plasmid maintenance in bacteria
Small regulatory RNA plays an important role in gene regulation in organisms from bacteria to mammals by controlling for example translation and/or mRNA stability and the list of known RNA regulation systems keeps increasing at a rapid pace [1,2,3]. sRNA regulation possesses characteristics that are distinct from protein regulation, in particular a threshold-linear response, which provides an ultrasensitive mechanism for regulatory switching, and the possibility of hierarchical crosstalk, which allows prioritizing of expression [4].Some of the best known sRNA regulation systems are related to plasmid replication and plasmid maintenance in bacteria
For the model described above, the following scenario is considered: the dynamics of the toxin-antitoxin system begin with a cell which has just acquired one or more copies of the plasmid, but has not yet synthesized any of its products, i.e. we start with m = s = c = p = 0
Summary
Small regulatory RNA (sRNA) plays an important role in gene regulation in organisms from bacteria to mammals by controlling for example translation and/or mRNA stability and the list of known RNA regulation systems keeps increasing at a rapid pace [1,2,3]. sRNA regulation possesses characteristics that are distinct from protein regulation, in particular a threshold-linear response, which provides an ultrasensitive mechanism for regulatory switching, and the possibility of hierarchical crosstalk, which allows prioritizing of expression [4].Some of the best known sRNA regulation systems are related to plasmid replication and plasmid maintenance in bacteria. When a progeny cell becomes plasmid-free through cell division, synthesis of both toxin mRNA and antitoxin sRNA are stopped. By inducing a gene encoding a competitor mRNA (on the same or another plasmid or on the chromosome) that can bind to the antitoxin sRNA and allows toxin mRNA to exist in free form, a similar increase in toxin concentration can be induced as with plasmid loss, which may lead to the killing of the cell.
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