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Stress-Induced Mutagenesis in Bacteria and the Regulation of Evolvability.   Susan M. Rosenberg^1-4, Rebecca Ponder¹, Albert He², Natalie C. Fonville^1,4, Janet Gibson¹, Caleb Gonzalez^1,4 and P.J. Hastings¹,    Departments of ¹Molecular and Human Genetics, 2Biochemistry and Molecular Biology, and ³Molecular Virology and Microbiology, and ⁴Interdepartmental Graduate Program in Cell and Molecular Biology, and Baylor College of Medicine, Houston, Texas

Stress-induced mutations, described in various bacteria and yeasts, are mutations induced in cells under growth-limiting stress. Some of the mutations formed may relive the stress and allow cell survival, potentially accelerating evolution under stress. Stress-induced mutagenesis may fuel tumor progression and resistance, antibiotic resistance and biological evolution generally. We have elucidated a mechanism of stress-induced mutagenesis in E. coli. In the E. coli Lac assay for starvation-stress-induced mutagenesis, we demonstrate that the mutations result from error-prone DNA double-strand-break repair. We show that this occurs specifically during stress because there is a switch in the fidelity of double-strand-break repair via homologous recombination during stress. The switch is controlled by the stationary-phase- or general-stress response controlled by the RpoS ( S) transcriptional activator. The mutagenic repair under stress involves use of the error-prone, Y-family DNA polymerase DinB, a member of a broadly conserved DNA polymerase family with four homologues including one orthologue in humans. Coupling mutagenesis to the RpoS-controlled (and the SOS DNA-damage) stress responses limits mutagenesis in time, to times when cells are poorly adapted to their environment, i.e., are stressed. We suggest that coupling mutagenesis to double-strand-break repair could represent an evolutionary/regulatory strategy that limits mutagenesis in genomic space to regions near (potentially rare, spontaneous) double-strand-breaks. Because most mutations are neutral or deleterious, limiting mutagenesis in genomic space could allow rare cells that acquire an adaptive mutation to survive, having ruined less of their genomes, and could also allow concerted evolution within genes and gene clusters. This strategy appears likely to have evolved independently and/or by conservation in other bacterial stress-induced mutation responses, in yeast, and in the human immune system.