Mutation As a Stress Response

MUTATION AS A STRESS RESPONSE

Susan M. Rosenberg, Rebecca G. Ponder, Mary-Jane Lombardo, Janet Gibson, Albert He, Pooja Rohatgi, Megan N. Hersh, Ildiko Aponyi. Mellanie P. Ray, Natalie Fonville, Jeanine M. Pennington, Christophe Herman and P. J. Hastings

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

In starving cells of the bacterium Escherichia coli, a special mutagenic program is induced that increases mutations, some of which can allow survival of the stress (adaptive mutations). Both polymerase-error-style point mutations (small frameshift mutations and base substitutions) and gene amplifications are induced. The point-mutagenesis requires at least three stress responses: the SOS DNA damage response, the RpoS- (sigma S)-controlled general stress response to starvation, stationary phase, oxidative, osmotic, cold-shock and acid stresses, and an E. coli heat-shock/protein-stress response. We suggest that such multilayered control by stress responses severely limits the dangerous process of global mutagenesis to times of stress, when organisms are poorly adapted to their environments: that stress responses are the signalers of poor adaptation that initiate genetic change mechanisms that are often deleterious, but sometimes result in an adaptive mutation. A second level of control is spatial: both the point mutations and the amplifications are also induced by DNA double-strand breaks (DSBs). We show that stress-induced point mutagenesis is caused by a switch from high-fidelity to error-prone DSB repair controlled by RpoS, using the special error-prone DNA polymerase, DinB/Pol IV. DNA near a DSB is mutated but another molecule is not. We suggest that coupling of stress-induced mutagenesis to DSB-repair further regulates and limits mutagenesis by restricting it to potentially small fractions of the genome, those in which DSBs are being repaired. This could be a regulatory strategy that both reduces deleterious mutations in cells that acquire a rare adaptive mutation, and potentially facilitates concerted evolution of genes and gene clusters. The themes of control by stress responses, and coupling to DSB-repair suggest a strongly limited and regulated mechanism that, though random, minimizes damage and maximizes potential benefit of increasing mutation rate in response to stress.