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

• Published in: Science (American Association for the Advancement of Science) Vol. 351; no. 6277; pp. 1094 - 1097
• Main Authors: Uphoff, Stephan, Lord, Nathan D., Okumus, Burak, Potvin-Trottier, Laurent, Sherratt, David J., Paulsson, Johan
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 04-03-2016; The American Association for the Advancement of Science
• Subjects: Alkylation; Cells; DNA damage; DNA Damage - genetics; DNA Mismatch Repair - drug effects; DNA Mismatch Repair - genetics; Enzyme Activation; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli - genetics; Escherichia coli Proteins - metabolism; Genetics; Methyl Methanesulfonate - pharmacology; Mutagens - pharmacology; Mutation; Mutation Rate; O-Methylguanine-DNA Methyltransferase - metabolism; Stochastic control theory; Stochastic Processes; Transcription Factors - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aac9786

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.