Gene expression noise randomizes the adaptive response to DNA alkylation damage in E. coli

Abstract

DNA damage caused by alkylating chemicals induces an adaptive response in Escherichia coli cells that increases their tolerance to further damage. Signalling of the response occurs through methylation of the Ada protein which acts as a damage sensor and induces its own gene expression through a positive feedback loop. However, random fluctuations in the abundance of Ada jeopardize the reliability of the induction signal. I developed a quantitative model to test how gene expression noise and feedback amplification affect the fidelity of the adaptive response. A remarkably simple model accurately reproduced experimental observations from single-cell measurements of gene expression dynamics in a microfluidic device. Stochastic simulations showed that delays in the adaptive response are a direct consequence of the very low number of Ada molecules present to signal DNA damage. For cells that have zero copies of Ada, response activation becomes a memoryless process that is dictated by an exponential waiting time distribution between basal Ada expression events. Experiments also confirmed the model prediction that the strength of the adaptive response drops with increasing growth rate of cells.