A fundamental challenge of biology is to understand the integrated operations of a cell, that lead it to double precisely, all its components during a single generation. Our studies of the biosynthesis of ribosomes in the yeast Saccharomyces cerevisiae have led to the unexpected finding that the emphasis of ribosomes is dependent on the continued synthesis of the cell's membranes. Our view is that this represents an example of the regulatory circuits between different macromolecular components of the cells, circuits that must be present to ensure balanced growth, but that have been generally unrecognized. This process of ribosome synthesis requires the coordinated synthesis of rRNA from greater than 100 genes, and of ribosomal proteins from more than 75 genes. The study of its regulation has led to profound biological insights. This proposal will combine genetic and biochemical techniques to explore the regulatory circuit between membrane synthesis and ribosome synthesis by asking: How does a defect in membrane synthesis generate a signal? Does it involve the plasma membrane? What is the nature of the signal? Does this regulatory circuit coincide with or intersect with other known regulatory circuits? What elements of ribosomal RNA and ribosomal protein genes recognize the signal? What other genes are regulated via the same pathway? We will search for mutant cells in which this regulatory circuit is defective, with the aim of identifying components of the circuit. In addition, studies will continue on the properties of a DNA binding protein, Reb1p, that is involved in the transcription of ribosomal RNA and probably in its regulation. 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 a 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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