Global mistranslation facilitates sampling of beneficial mutations under stress

Abstract

11Mistranslation is typically deleterious, but can sometimes be beneficial. Although a specific 12 mistranslated protein can confer a short-term benefit in a particular environment, the prevalence of high 13 global mistranslation rates remains puzzling given the large overall cost. Here, we show that generalized 14 mistranslation enhances early E. coli survival under various forms of DNA damage, because it leads to 15 early activation of the DNA damage-induced SOS response. Mistranslating cells therefore maintain 16 larger populations, facilitating later sampling of critical beneficial mutations. Thus, under DNA 17 damage, both basal and induced mistranslation (through genetic or environmental means) increase the 18 number of genetically resistant and phenotypically persistent cells. Surprisingly, mistranslation also 19 increases survival at high temperature. This wide-ranging stress resistance relies on Lon protease, which 20 is revealed as a key effector that induces the SOS response in addition to alleviating proteotoxic stress. 21The new links between error-prone protein synthesis, DNA damage, and generalised stress resistance 22 indicate surprising coordination between intracellular stress responses, and suggest a novel hypothesis 23 to explain high global mistranslation rates. 24 25