Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation

To have or have not determines DNA repair Cells presumably try to protect DNA from damage at all costs. But Uphof et al. show that they do not, because the cost is too high. Single-molecule and single-cell measurements show that the DNA repair enzyme Ada, which also regulates its own expression, was present in such low amounts in E. coli that stochastic variation led to some cells having none of the protein at all. Such cells undergo increased mutagenesis, which could be beneficial in circumstances in which increased genetic heterogeneity is required for adaptation. The expression of large amounts of such a DNA-altering protein was also toxic. Science, this issue p. 1094 Nongenetic heterogeneity can lead to genetic variation. Cells rely on the precise action of proteins that detect and repair DNA damage. However, gene expression noise causes fluctuations in protein abundances that may compromise repair. For the Ada protein in Escherichia coli, which induces its own expression upon repairing DNA alkylation damage, we found that undamaged cells on average produce one Ada molecule per generation. Because production is stochastic, many cells have no Ada molecules and cannot induce the damage response until the first expression event occurs, which sometimes delays the response for generations. This creates a subpopulation of cells with increased mutation rates. Nongenetic variation in protein abundances thus leads to genetic heterogeneity in the population. Our results further suggest that cells balance reliable repair against toxic side effects of abundant DNA repair proteins.