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At the molecular level, all cellular processes are subject to random fluctuations, affecting every aspect of cell function. Considering the importance of genome maintenance, one would expect DNA repair to be robust to noise and show little random variation. In contrast, we uncovered drastic heterogeneity when we studied the Ada DNA damage response in E. coli at single-molecule and single-cell resolution. Ada activation protects cells against toxic and mutagenic effects of DNA alkylation damage. Unexpectedly, gene expression noise results in a subpopulation of cells without any Ada molecules, which randomizes activation of the damage response. This causes accumulation of mutagenic lesions and increases mutation rates in a subpopulation of cells. Therefore, phenotypic variation can be the source of genetic heterogeneity.