Role of the SOS Response in Stationary-Phase Hypermutation: A Model for Mutation in Oncogenesis and Chemotherapeutic Drug-Resistance

The SOS response of Escherichia coli is the prototypic DNA damage repair and cell cycle checkpoint control system. It is analogous to checkpoint control in eukaryotes. The SOS response includes blocking the cell cycle, global mutagenesis via more than one mechanism, and up regulation of DNA repair and recombination functions. Adaptive mutation is a mutational program in non-growing cells subjected to starvation and so is also a temporary mutagenic response to environmental stress. It entails global hypermutation, and previously, the signal transduction pathway from the environment to the DNA was unknown. Here we demonstrate that adaptive mutation of a lac allele in E. coli is under control of the SOS response. Although homologous recombination and recombination protein RecA the prokaryotic homologue of hRad51 and other human DNA repair proteins are required for lac adaptive mutation, we find that SOS induced levels of components other than or in addition to RecA are also involved. We report a partial requirement for RecF, a recombination protein and SOS regulator, and find that the sole function of RecF in adaptive mutation is to allow SOS induction of SOS-controlled genes. We also report the discovery of an SOS-controlled factor that inhibits adaptive mutation, psiB. These results indicate that adaptive mutation is a tightly temporally regulated mutational response, controlled positively and negatively by the SOS system. In addition, we report preliminary results describing the role of damage-inducible DinB in adaptive mutation.