In a growing cell of Saccharomyces cerevisiae transcription of the ribosomal protein genes makes up 30 percent of the RNA polymerase II initiation events. Furthermore, the cell produces the 80 components of the ribosome in equimolar amounts. Thus, the synthesis of ribosomes requires not only the consumption of a major portion of the cell's resources, but also the delicate control necessary to avoid imbalance among the components. The production of ribosomes is regulated not only by the source of nutrients and other external factors, but also by intracellular signal transduction pathways that integrate the operations of the cell. This integration is evident from our observation that any defect in the secretory pathway, responsible for the synthesis of membranes, leads to a rapid repression of the synthesis of both ribosomal RNA and ribosomal protein genes. We propose to investigate the molecular basis of this regulation along two interlocking lines. (I) We will try to identify the 'signature' that identifies each of the 137 ribosomal protein genes, (a) through mutagenesis, chimeric promoters, etc., (b) by identifying the active sites, for this regulation, of the repressor activator protein Rap1p, (c) by using genome-wide expression assays to identify any ribosomal protein gene that is an 'outlier', i.e., is not coordinately regulated coordinately with the others, and for other sets of genes that might be regulated coordinately with the ribosomal proteins. (II) We will set up a genetic screen to identify mutants that no longer repress ribosome synthesis in response to a defect in the secretory pathway, hoping to identify participants (a) in the detection of the defect, (b) in the signal transduction pathway that notifies the nucleus, and (c) in the transcriptional apparatus that responds to that notification. Since growth depends on protein synthesis and protein synthesis depends on ribosome synthesis, the control of ribosome synthesis leads, in a very real sense, to the control of growth. Imbalance in the growth of cells is the cause of much disease. Our hope, and expectation, is that understanding the circuits that underlie the regulation of ribosome synthesis will lead to more effective intervention when an imbalance occurs.
| Gupta, Varun; Warner, Jonathan R (2014) Ribosome-omics of the human ribosome. RNA 20:1004-13 |
| Lee, Jaehoon; Moir, Robyn D; McIntosh, Kerri B et al. (2012) TOR signaling regulates ribosome and tRNA synthesis via LAMMER/Clk and GSK-3 family kinases. Mol Cell 45:836-43 |
| McIntosh, Kerri B; Bhattacharya, Arpita; Willis, Ian M et al. (2011) Eukaryotic cells producing ribosomes deficient in Rpl1 are hypersensitive to defects in the ubiquitin-proteasome system. PLoS One 6:e23579 |
| Warner, Jonathan R (2011) 18S rRNA: a tale of the tail. J Mol Biol 405:1-2 |
| Bhattacharya, Arpita; McIntosh, Kerri B; Willis, Ian M et al. (2010) Why Dom34 stimulates growth of cells with defects of 40S ribosomal subunit biosynthesis. Mol Cell Biol 30:5562-71 |
| Warner, Jonathan R; McIntosh, Kerri B (2009) How common are extraribosomal functions of ribosomal proteins? Mol Cell 34:3-11 |
| Bhattacharya, Arpita; Warner, Jonathan R (2008) Tbf1 or not Tbf1? Mol Cell 29:537-8 |
| McIntosh, Kerri B; Warner, Jonathan R (2007) Yeast ribosomes: variety is the spice of life. Cell 131:450-1 |
| Rudra, Dipayan; Mallick, Jaideep; Zhao, Yu et al. (2007) Potential interface between ribosomal protein production and pre-rRNA processing. Mol Cell Biol 27:4815-24 |
| Zhao, Yu; McIntosh, Kerri B; Rudra, Dipayan et al. (2006) Fine-structure analysis of ribosomal protein gene transcription. Mol Cell Biol 26:4853-62 |
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