Maturation of the Large Ribosomal Subunit in Yeast

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DESCRIPTION (provided by applicant): The ribosome is responsible for protein synthesis and is essential in all cells. Its faithful translation of the genetic code and the proper regulation of its activity are necessary for normal cell growth and development. Ribosome assembly is a complex and dynamic process and mechanisms must exist that ensure the correct assembly of ribosomes in order to maintain the fidelity of translation. In addition, ribosome biogenesis accounts for a large portion of the energy expenditure of a rapidly dividing cell and must be coordinated with the metabolic needs of a cell. Indeed, cell proliferation in humans requires upregulation of ribosome biogenesis. Thus, understanding the mechanisms regulating ribosome biogenesis will provide insight for the development of new tools for controlling cell proliferation in disease states. The delineation of fundamental cellular pathways such as ribosome biogenesis and translation is also necessary for the intelligent development of new drugs that are specific to their intended cellular targets without impinging on other cellular pathways. We recently identified the nuclear export pathway for the large ribosomal subunit in yeast. We showed that its export depends on the export adapter protein Nmd3p and the export receptor Crm1 and that this export pathway is conserved in human cells. In this proposal, we will expand on these initial findings using reagents that we have developed in our studies of NmdSp. This proposal will: 1) Address how the export adapter and its receptor assemble on the large ribosomal subunit to mediate export. 2) Elucidate the events required to release the export adapter from the subunit after delivery to the cytoplasm. 3) Determine the function of Arx1 p and Reilp, two functionally related proteins that act at the polypeptide exit tunnel on the nascent large ribosomal subunit during export and as it enters the cytoplasmic pool of active subunits.