Global mistranslation facilitates sampling of beneficial mutations under stress

Abstract

Mistranslation is typically deleterious, but can sometimes be beneficial. Although a specific mistranslated protein can confer a short-term benefit in a particular environment, the prevalence of high global mistranslation rates remains puzzling given the large overall cost. Here, we show that generalized mistranslation enhances early E. coli survival under various forms of DNA damage, because it leads to early activation of the DNA damage-induced SOS response. Mistranslating cells therefore maintain larger populations, facilitating later sampling of critical beneficial mutations. Thus, under DNA damage, both basal and induced mistranslation (through genetic or environmental means) increase the number of genetically resistant and phenotypically persistent cells. Surprisingly, mistranslation also increases survival at high temperature. This wide-ranging stress resistance relies on Lon protease, which is revealed as a key effector that induces the SOS response in addition to alleviating proteotoxic stress. The new links between error-prone protein synthesis, DNA damage, and generalised stress resistance indicate surprising coordination between intracellular stress responses, and suggest a novel hypothesis to explain high global mistranslation rates.