This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. All organisms must be capable of responding rapidly and specifically to a variety of internal and external stressors, such as sudden changes in temperature, nutrient starvation, DNA damaging agents, or the presence of heavy metals or other environmental contaminants. Even elements that are normally required by cells in trace amounts, such as copper and zinc, become toxic at high levels. Sublethal levels of heavy metal contaminants can also lead to serious problems with continuous exposure. Organisms must be able to carefully balance the levels of these trace elements at the cellular level, by excluding, exporting, or safely sequestering them when they reach toxic levels, while retaining the essential minimal concentrations needed for normal cellular functions. Cells must also have means of importing these same elements under conditions of starvation. Proper homeostatic control requires rapid activation of genes involved in the response to surfeit or starvation. However, there must also be precise adjustment of the final levels of gene expression, in order to fine-tune the response to the challenge to homeostasis. The activation pathways for many stress-responsive genes have been extensively characterized in yeast. The yeast CUP1 gene encodes a metallothionein, and is a well-characterized model for the transcriptional response to toxic metal stress, particularly the response to cadmium and copper. Work in my laboratory has focused on the mechanisms by which CUP1 is activated and subsequently down-regulated during the response to copper exposure. We are currently studying the roles of chromatin structure and antisense transcription in the control of the copper response.
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