Hepatic delta-aminolevulinate (ALA) synthase, the first and normally rate limiting enzyme in heme biosynthesis is regulated by heme by at least two mechanisms. One is the destabilization of the ALA synthase mRNA in the presence of hem. The other is the reduction of mitochondrial import of Ala synthase from the cytosol into the mitochondria. Although mRNA destabilization has been described for both chicken and rat, the proximate mechanisms, including cis acting RNA sequences and trans acting factors, such as RNA binding proteins, have not yet been identified and characterized. This research specifically proposes to identify and characterize the cis acting elements which regulate ALA synthase mRNA stability in the presence of heme. The indentification of the sequences will be assessed using the following criteria: 1) deletion of the sequences abolish the heme-mediated mRNA destabilization response; and b) incorporation of the sequence of interest within an unrelated mRNA renders the chimeric molecule responsive to heme- mediated mRNA destabilization. Obtaining information regarding the cis-acting elements within the ALA synthase mRNA is the first step in understanding the molecular mechanisms that are used by a cell to regulation hepatic ALA synthase activity and may have implications for understanding RNA processing in general.
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