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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM035949-11
Application #
2178153
Study Section
Special Emphasis Panel (NSS)
Project Start
1985-06-01
Project End
1998-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
11
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Nomura, Masayasu (2011) Journey of a molecular biologist. Annu Rev Biochem 80:16-40
Anderson, Susan J; Sikes, Martha L; Zhang, Yinfeng et al. (2011) The transcription elongation factor Spt5 influences transcription by RNA polymerase I positively and negatively. J Biol Chem 286:18816-24
Nomura, Masayasu (2009) Switching from prokaryotic molecular biology to eukaryotic molecular biology. J Biol Chem 284:9625-35
Hontz, Robert D; French, Sarah L; Oakes, Melanie L et al. (2008) Transcription of multiple yeast ribosomal DNA genes requires targeting of UAF to the promoter by Uaf30. Mol Cell Biol 28:6709-19
French, Sarah L; Osheim, Yvonne N; Schneider, David A et al. (2008) Visual analysis of the yeast 5S rRNA gene transcriptome: regulation and role of La protein. Mol Cell Biol 28:4576-87
Oakes, Melanie L; Johzuka, Katsuki; Vu, Loan et al. (2006) Expression of rRNA genes and nucleolus formation at ectopic chromosomal sites in the yeast Saccharomyces cerevisiae. Mol Cell Biol 26:6223-38
Oakes, Melanie L; Siddiqi, Imran; French, Sarah L et al. (2006) Role of histone deacetylase Rpd3 in regulating rRNA gene transcription and nucleolar structure in yeast. Mol Cell Biol 26:3889-901
Schneider, D A; French, S L; Osheim, Y N et al. (2006) RNA polymerase II elongation factors Spt4p and Spt5p play roles in transcription elongation by RNA polymerase I and rRNA processing. Proc Natl Acad Sci U S A 103:12707-12
Schneider, David A; Nomura, Masayasu (2004) RNA polymerase I remains intact without subunit exchange through multiple rounds of transcription in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 101:15112-7
Kobayashi, Takehiko; Horiuchi, Takashi; Tongaonkar, Prasad et al. (2004) SIR2 regulates recombination between different rDNA repeats, but not recombination within individual rRNA genes in yeast. Cell 117:441-53

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