Small ribonucleoproteins (RNPs) are essential components of all eukaryotic cells. As the core elements of the spliceosome, small RNPs are required for pre-messenger RNA splicing. The basic mechanics of splicing are fairly well-understood, however, the biogenesis of the small nuclear (sn)RNPs that carry out this process is relatively unclear. The long-term goal of this proposal is to understand the molecular mechanisms that govern the biogenesis and subcellular localization of snRNPs. In short, we seek to uncover the process by which snRNPs are packaged, transported and delivered to their sites of action. The initial phases of snRNP biogenesis begin in the cytoplasm, following nuclear export of the snRNA transcript. Assembly into stable particles is thought to be mediated by the Survival of Motor Neurons (SMN) protein complex in collaboration with the Protein Arginine Methyltransferase 5 (PRMT5) complex. Subsequently, these small RNPs are imported back into the nucleus. Defects in the assembly of Sm-class small RNPs are associated with a disorder called Spinal Muscular Atrophy (SMA). Patients with SMA typically die in early childhood. Although snRNP biogenesis is compromised in patient-derived cells, the underlying cause of the SMA phenotype is not understood. Mutations in other snRNP biogenesis genes may phenocopy SMA. Thus a detailed understanding of snRNP metabolism is essential not only to the study of RNA processing, but will also be important in developing treatments for neuromuscular disease. To gain insight into these processes, we have developed a Drosophila model system.
Specific Aims of this proposal are: (1) to characterize the function of the SMN complex in snRNP biogenesis and neuromuscular development, (2) to understand the role played by the snRNA transporter, PHAX, in development of the neuromuscular system and to assay the consequences of mutations in phax and smn on snRNP function, and (3) to investigate the activity of the PRMT5 complex in the biogenesis of a potentially novel class of Sm-RNPs. Lay Summary: Spinal Muscular Atrophy (SMA) is a common genetic disease that strikes young children;most of them die before reaching the age of two years. The gene responsible for this disease has been identified, but the underlying basis for how the gene functions in the cell is not known. To ultimately develop a treatment, we first need to understand the normal function(s) of the disease gene and its partner genes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Nuclear Dynamics and Transport (NDT)
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Bender, Michael T
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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