The long-term objective of the proposed research is to understand the mechanism by which mRNAs are exported out of the nucleus. The process of mRNA export includes: proper processing, packaging into protein-RNA complexes, targeting to and movement through the nuclear pore complex and release into the cytoplasm for translation. A transport machinery distinct from that for protein export has been proposed for mRNAs. As with protein import and export, mRNA export can also be regulated by, for example, growth conditions and viral infection.
The Specific Aims are to determine how: 1) mRNAs are co- transcriptionally recruited for export; 2) mRNAs are recognized in the nucleus by certain RNA binding proteins; 3) mRNAs are selectively exported under conditions of stress; and 4) protein methylation of RNA binding proteins at arginine affects their activity. Defects in mRNA metabolism that can affect transport are associated with a number of diseases thus contributing to the health-relatedness of the project. For example, splicing and 3' end formation are associated with a number of diseases including metastatic cancers, muscular dystrophy and amyotrophic lateral sclerosis. In addition, some viruses exploit the endogenous nuclear transport machinery in order to propagate - in some cases by inhibiting export of host in favor of viral messages. Methylation of RNA and DNA binding proteins at arginine has recently emerged as important for many levels of regulation including viral RNA export, response of cells to interferon and the action of certain RNA binding proteins in motor neuron degeneration in spinal muscular atrophy. Lastly, arginine-methylated proteins such as hnRNPs and myelin basic protein are prominent in autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis. It may be that modified arginine elicits special recognition properties that lead to exacerbation of autoimmune diseases.
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