The control of gene expression at the post-transcriptional level is a fundamental problem in biology, with relevance to cancer. The basic mechanisms for the regulation of alternative splicing of cellular and viral genes in different tissues, developmental stages, or in response to external signals, will be investigated. We will carry out detailed structural and functional studies of hnRNP A1 and its derivatives, focusing on its nucleic acid-binding properties' its activities in alternative 5' splice-site selection, splicing silencing and telomere-length regulation, and the regulation of its localization and activity in response to genotoxic stress. We will carry out genetic screens in cultured mammalian cells to identify protein components involved in the fidelity of pre-mRNA splicing. Finally, we will continue the development of new technology involving rational design of compounds that mimic one of the activities of SR proteins, the activation of splicing via exonic splicing enhancers. These compounds will be tested for their ability to correct specific splicing defects caused by mutations in cancer susceptibility genes, and to modulate the expression of alternatively spliced isoforms of an apoptosis gene. These studies are directly relevant to the overall goals of the Program Project. As global regulators of alternative pre-mRNA splicing, hnRNP A1 and its antagonists, the SR proteins, may be responsible for the observed aberrant patterns of mRNA expression of numerous genes in transformed cells. Among potential targets of these regulators are several critical genes involved in the establishment or maintenance of the transformed phenotype, or in progression of malignancy. Regulation of alternative splicing is responsible for generating oncongenic and non-oncogenic forms of many cellular and viral oncogenes. Therefore, a better understanding of the basic mechanisms of alternative splicing regulation, and of the fidelity of this process, may lead to the design of drugs to specifically affect the synthesis of particular protein isoforms that play critical roles in tumorigenesis.
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