Gene Regulation by Oxidative Stress in Bacillus Subtilis

点击翻译按钮获取中文摘要

All organisms must obtain a specific set of trace metals from their environment yet these same metals, if present in excess, can lead to toxicity often by catalyzing the formation of toxic free radicals. Iron and copper, in particular, can aggravate oxidative stress by contributing to the generation of highly reactive hydroxyl radicals. In contrast, manganese and zinc can actually protect cells against oxidative stress. Bacillus subtilis contains two regulons that are selectively induced by peroxide stress (PerR and OhrR) and at least two regulons induced by nitric oxide (PerR and Fur). This project focuses on two regulators that respond to reactive oxygen species: PerR and OhrR. The peroxide regulon (PerR) repressor is structurally related to Fur but PerR functions physiologically as a sensor of peroxidative stress, rather than metal ion starvation. It is proposed that PerR, together with a metal bound cofactor, reacts with hydrogen peroxide to generate an inactive repressor. The nature of the change(s) in PerR that lead to derepression will be defined. The OhrR protein contains a highly reactive cysteine residue that reacts with organic peroxides to generate a cysteine-sulfenic acid derivative. This protein modification inactivates the repressor leading to expression of an organic hydroperoxide resistance gene. The effects of cysteine oxidation on OhrR function will be investigated. The proposed studies will provide insights into how proteins function as sensors of reactive oxygen/nitrogen species. The presence of related regulators in diverse bacteria argues that the paradigms established by a detailed characterization of these proteins will have far-reaching implications.