Gene Regulation by Oxidative Stress in Bacillus subtilis

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This project addresses the biological roles and mechanisms of two bacterial regulatory proteins that respond to reactive oxygen species: Bacillus subtilis PerR and OhrR. The peroxide regulon (PerR) repressor is a member of the Fur (ferric uptake regulator) family of metal-dependent repressor proteins. PerR functions as a sensor of peroxide stress by reacting with hydrogen peroxide to generate hydroxyl radical, which modifies histidine residues that coordinate the bound Fe2+ cofactor. The resulting oxidized protein is inactive for DNA-binding. The OhrR protein contains a highly reactive cysteine residue that reacts with organic peroxides to generate a cysteine-sulfenic acid that then reacts with low molecular mass thiols to generate mixed-disulfides. Oxidized OhrR also forms a sulfenyl-amide derivative. These protein modifications inactivate the repressor leading to expression of organic hydroperoxide resistance. This project addresses the detailed mechanisms by which protein oxidation regulates the activity of these two proteins. This research will determine whether oxidized PerR is degraded, or the subject of a novel protein repair pathway. The effects of protein oxidation on OhrR will be investigated, and proteins that contribute to reactivation of OhrR will be defined. Related regulatory proteins are present in diverse bacteria, including important plant and animal pathogens where they function to regulate genes important for virulence. This research will address fundamental aspects of protein chemistry and oxidation. Protein oxidation is important in the life of all cells and is thought to contribute to ageing and numerous age-related diseases. The project will train students at all levels in genetic and protein chemistry techniques.