Since the rate of growth of a cell depends on the synthesis of proteins, and the synthesis of proteins depends on ribosomes, the regulation of growth must ultimately depend on the regulation of the synthesis of ribosomes, which consumes a large fraction of the cell's resources. Thus our study of the regulation of ribosome synthesis is fundamental to the understanding of growth control. We will attempt to determine how 137 ribosomal protein genes, encoding 78 ribosomal proteins and responsible for some 30 percent of the cell's mRNAs, are transcribed to such a high degree, with such quantitative precision, and with such coordinate regulation in S. cerevisiae. The critical transcription factor, Rap1, is responsible both for activating and for silencing the RP genes, Our hypothesis is that the entire upstream sequence has evolved to meet these demands, implying interaction between activator and promoter elements. These studies will be based on a systematic analysis of the functional interaction of Rap1 sites found on ribosomal protein genes with their own or with others' proximal promoter regions, and vice versa, testing the Rap1 sites found in other genes or in the telomeres. Of particular value is that we can independently assay the response to at least three signaling pathways, PKA, PKC, and TOR, as well as heat shock and other stresses that affect ribosome synthesis. We will dissect Rap1, itself, including determining the role of the DNA binding region, asking whether specific regions can 'squelch' Rap1 function, and determining the post-translational modifications of Rap1 that might play a role in this regulation. A new project arises from our recent genetic results that have drawn our attention to an important but neglected area of cell physiology, not only for S. cerevisiae, but for all cells, the identification and degradation of mal-assembled or incomplete ribosomal subunits, that, if left intact, could clog the pathways for translation or ribosome assembly. We propose an experiment to ask whether there is functional proofreading of completed ribosomes. We will examine the several parts of both the protein degradation pathway and the RNA degradation pathway to determine which is involved in this important task. We propose a mutant screen to identify key players.
| 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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