REGULATION OF MRNA STABILITY IN MAMMALIAN CELLS

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The goal of this work is to understand how the decay rates of mRNAs are regulated in mammalian cells and how changes in mRNA half-life influence the cellular responses to growth and differentiation factors, carcinogens, and environmental stress. During the past five years, interest in mRNA stability has increased substantially, with the recognition of the links between cytoplasmic mRNA half-life and gene expression. the regulation of cytoplasmic decay rates is particularly important for mRNAs whose levels fluctuate rapidly in response to various stimuli. This proposal focuses on the regulation of two mRNAs, histone and c-myc, and on the destabilization of host mRNAs in cells infected with herpes simplex virus type 1 (HSV-1). In vitro assays plus gene transfection experiments will be used to identify the enzymes that degrade histone and c-myc mRNAs and to characterize the regulatory factors that influence their decay rates. From these two specific cases, we hope to draw some general conclusions about how the half-lives of other mRNAs are regulated. An HSV-1-encoded protein induces the destabilization of almost every host mRNA in infected cells, apparently by activating a potent mRNase activity encoded by the host. We hope to characterize the mRNase and to determine the mechanism by which it is induced. Then we can identify those factors that repress the mRNase in uninfected cells and determine the function of the mRNase.