The ribosome, the machinery essential for protein synthesis, obviously plays a key role in cell growth and its synthesis is intimately connected to the regulation of cell proliferation both in prokaryotic and eukaryotic cells. It is well known that in bacteria, the cellular content of ribosomes is roughly proportional to the growth rate of cells under various nutritional conditions. Our goal is to understand how bacteria regulate the production of ribosomes and their growth rate. We have previously discovered that ribosomal protein synthesis and ribosome assembly are coupled such that when ribosomal protein synthesis exceeds the rate of ribosome biosynthesis, certain key ribosomal proteins act as inhibitors that prevent the further translation of their own mRNA. This feedback regulation model can account for coordinate and balanced synthesis of most of the ribosomal protein components. In addition, we have recently found that the synthesis of rRNA (and tRNA) is negatively feedback regulated by products of rRNA operon, ribosomes, and that the negative feedback signal (which is yet to be identified) is probably generated by excess translational activities of ribosomes. This feedback regulation of rRNA synthesis accounts for the growth- rate-dependent control of ribosome synthesis. We will continue to study detailed mechanisms involved in the translational feedback regulation of ribosomal protein synthesis, and those involved in the feedback regulation of rRNA synthesis. Both in vivo and in vitro approaches will be used. In vivo approaches will include isolation of mutants with defects in translational regulation and those with defects in growth-rate-dependent control of rRNA synthesis. In addition, we will study the regulation of the synthesis as well as the function of RNA polymerase and other protein factors involved in the transcription and translation apparatus in connection with the regulation of growth. Finally, we now intend to study the regulation of ribosome synthesis in yeast. We plan to isolate temperature-sensitive mutants of RNA polymerase I and their suppressors. Studies on these mutants as well as factors and structures associated with RNA polymerase I will be done to understand the regulation of rRNA (and ribosome) synthesis in yeast cells and in eukaryotic cells in general.
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