The long term objective of this proposal is to elucidate the general mechanisms responsible for the specificity of splice site selection during nuclear pre-mRNA splicing in mammalian cells. The proposed experiments will address the role of general protein splicing factors on the selection of specific 5' and 3' splice sites in cellular and viral pre-mRNAs that are constitutively or alternatively spliced. New human protein splicing factors will be identified and isolated by homology to their yeast counterparts. The structure and function of selected protein splicing factors will be examined in detail with respect to their roles in specific steps of splicing and in splice site selection. The expression of genes for protein splicing factors that affect splice site selection in vitro in a concentration-dependent manner will be measured in different cell lines and tissues. The possible regulation of this expression at the RNA and protein level by viral gene products and by oncogenic transformation will be studied. Molecular genetic, immunochemical, and biochemical approaches will be used to express recombinant splicing factors in bacteria, to study their structure and function, and to measure the expression of the corresponding genes in mammalian cells. These studies may uncover important roles for a subset of protein splicing factors in regulating the expression of numerous alternatively spliced viral and cellular genes, and in cellular reprogramming by viral gene products and by oncogenic transformation.
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