Ultrasensitive response in bacterial replication initiation

Bacteria are able to coordinate cell growth and genome replication in different growth conditions. The DNA-binding protein DnaA is responsible for determining initiation of replication, thereby playing a central role in this coordination. Theoretical and experimental studies have shown that stability of the cell cycle requires an ultrasensitive response, i.e., a sharp dependence of the initiation firing rate on the cell volume. However, the source of such ultrasensitivity remains elusive. In this work, we elucidate how the structure and binding affinities of the DnaA regulatory system determine its ultrasensitive response. Our theory sets precise constraints on binding parameters, that are necessary for cell cycle stability. Our findings show how the variety of regulatory mechanisms of the DnaA system are required for ultrasensitivity across growing conditions.