The long-term goal of this research project is to understand the basic principles that govern mRNA degradation, a process that plays a key role in controlling gene expression in all organisms. The immediate goal is to elucidate the mechanism of action of diadenosine tetraphosphate, a stress-induced alarmone that has been implicated in a variety of cellular phenotypes important for bacterial pathogenesis, including invasiveness, biofilm formation, motility, replication, and antibiotic tolerance. Our recent discovery that mRNA degradation is impeded in Escherichia coli cells whose Ap4A concentration is elevated as a result of the absence of the major Ap4A hydrolase ApaH suggests a possible basis for these cellular properties. The objective of this research proposal is to determine the mechanism by which Ap4A and ApaH influence mRNA decay and the breadth of their impact. Achieving this objective will require the use of a variety of molecular biological, biochemical, and genetic methods. The knowledge gained from these studies will provide fundamental insights into a novel aspect of gene regulation that appears to be important for bacterial pathogenesis.
The proposed research will address a novel aspect of how bacteria respond to stress and the mechanism by which it impacts the lifetime of messenger RNA. The knowledge thereby acquired is expected to be of value in understanding the regulatory processes that govern bacterial pathogenesis and antibiotic tolerance. The methods and concepts developed in the course of these studies may also be useful for elucidating how messenger RNA degradation helps to ensure proper levels of gene expression in healthy human cells.
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