The long-term goal of this project is to understand the nuclear export of the eukaryotic small (40S) ribosomal subunit. Ribosomes are among the largest and most complex ribonuclear- protein machines assembled in eukaryotes, and their export, from the nucleus where they are assembled, to the cytoplasm where they function, presents some unusual challenges for cells. First, ribosomes are huge and very hydrophilic compared to the dimensions and hydrophobicity of the nuclear pore. Second, like processed pre-mRNAs, export must be coupled to final assembly to prevent the premature export of incomplete subunits. Export receptors may be key to solving /regulating both these issues. Recently, significant progress has been made towards identifying the export receptors for the large (60S) ribosomal subunit, but the factor(s) necessary to export the small (40S) subunit remain largely undefined. We propose to address this in two ways. 1) We have assembled considerable evidence implicating Ltv1 in the nuclear export of pre-40S subunits;the hypothesis that Ltv1 functions as a Crm1 adapter for 40S export will be tested. 2) Export of the 40S is likely to require multiple export factors. We will use a genetic screen to identify and characterize other 40S export factors. The results of this project are expected to have significance beyond understanding ribosome synthesis in yeast. Ribosome biogenesis is highly conserved in eukaryotes, and changes in ribosome biogenesis, both qualitative and quantitative, are among the most important molecular alterations in cancer cells. Within this context, it is important to understand small subunit export for several reasons. First, the small subunit controls translation initiation, the rate-limiting step in protein synthesis, and a step at which deregulation has been shown to result in oncogenic transformation. Second, nucleocytoplasmic transport of the small subunit could be a therapeutic target in neoplastic disease, but a better understanding of the details of transport of different cargoes will be required before sufficiently specific and effective inhibitors can be developed. Finally, from a basic science perspective, it will be important to understand small subunit export to discern whether there are general principles for exporting large hydrophilic cargoes through the nuclear pore.
We plan to continue our studies of ribosome biogenesis and export in yeast. The biogenesis of ribosomes is tightly coupled to cell growth;indeed, recent data suggest that changes in ribosome biogenesis may be among the most important molecular alterations in cancer cells. A better understanding of the details of ribosome biogenesis and export could potentially identify new therapeutic targets in the fight against cancer.
|Merwin, Jason R; Bogar, Lucien B; Poggi, Sarah B et al. (2014) Genetic analysis of the ribosome biogenesis factor Ltv1 of Saccharomyces cerevisiae. Genetics 198:1071-85|
|Fassio, Claire A; Schofield, Brett J; Seiser, Robert M et al. (2010) Dominant mutations in the late 40S biogenesis factor Ltv1 affect cytoplasmic maturation of the small ribosomal subunit in Saccharomyces cerevisiae. Genetics 185:199-209|
|Seiser, Robert M; Sundberg, Alexandra E; Wollam, Bethany J et al. (2006) Ltv1 is required for efficient nuclear export of the ribosomal small subunit in Saccharomyces cerevisiae. Genetics 174:679-91|
|Loar, Jesse W; Seiser, Robert M; Sundberg, Alexandra E et al. (2004) Genetic and biochemical interactions among Yar1, Ltv1 and Rps3 define novel links between environmental stress and ribosome biogenesis in Saccharomyces cerevisiae. Genetics 168:1877-89|