title: Stochastic activation of a DNA damage response causes cell-to-cell mutation rate variation.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. stephan.uphoff@bioch.ox.ac.uk johan_paulsson@harvard.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Uphoff
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Lord
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Burak
authors.initials: B
authors.lastname: Okumus
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. Biophysics Ph.D. Program, Harvard Medical School, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Potvin-Trottier
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sherratt
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. stephan.uphoff@bioch.ox.ac.uk johan_paulsson@harvard.edu.
authors.forename: Johan
authors.initials: J
authors.lastname: Paulsson
mesh_terms: D000478:Alkylation; D004249:DNA Damage / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics*; D004789:Enzyme Activation; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D059645:Mutation Rate; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D013269:Stochastic Processes; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D029968:Escherichia coli Proteins; D009153:Mutagens; D014157:Transcription Factors; D008741:Methyl Methanesulfonate; C045675:Ada protein, E coli; D019853:O(6)-Methylguanine-DNA Methyltransferase