Cu/Zn superoxide dismutase (SOD!) is a well-conserved anti-oxidant enzyme present in virtually all eukaryotic cellsand tissues. While clearly important for oxidative stress, little is known about the biology of SODl underphysiologically relevant oxygen conditions. The overall goal of this research is to understand how SODl is controlledby changes in cellular redox and how SODl and its activator protein CCS maintain cell fitness over a range of oxygentensions. We identified CCS as the key activator of human SODl under atmospheric oxygen, but when oxygen levelsdrop, SODl is activated by a CCS independent pathway. We hypothesize this switch in SODl activation has evolvedas adaptation to varying redox environments of tissues and sub-cellular compartments, and we will address this usingboth yeast and mammalian expression systems. We identified the SODl disulfide as the target for redox control ofSOD], but how the disulfide is oxidized under hypoxic conditions without CCS is not clear. Yeast genetic screens willbe used to identity the trans-acting factors that work independent of CCS to target the disulfide and activate SOD].Cu/Zn SODl is not normally essential for aerobic life, but we observed that yeast sodl null mutants cannot thrive in airwhen levels of cytosolic phosphate rise. Phosphate-metal interactions may be key to this severe oxidative stress andthrough molecular/genetic approaches, we will explore the mechanism of phosphate mediated oxygen toxicity and howthis damage is ameliorated by SODl. Finally we observed an interesting effect of hypoxia on SODl and CCS. SODlactivity and protein levels drop dramatically during hypoxia in yeast, while CCS levels remain high. We found that thishypoxic loss of SODl can be important for anaerobic cell survival. Hypoxia can trigger mitochondrial production ofreactive oxygen and nitrogen species for signaling, and we will test the hypothesis that loss of mitochondrial SODl is acritical component of this hypoxic signaling. The rationale for maintaining CCS with low oxygen is not clear, but weobserve an effect of CCS loss on genomic stability even under anaerobic conditions. We will continue to explore thisnovel effect of CCS on chromatin using molecular-genetic strategies. All together, these studies promise to shed newimportant light into the biology of an important anti-oxidant enzyme and its activator protein CCS.
A large number of human disorders Including diseases of the heart, lung and nervous systems have beenattributed to damage from reactive oxygen. At the extreme opposite, low levels of oxygen or reactive oxygenare critical in vascular remodeling in cancer. SODl represents a major means for controling reactiveoxygen. Hence, studies on the biology of S0D1 and CCS under a range of oxygen conditions are relevant.
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