The ribosome is responsible for protein synthesis and is essential in all cells. Its faithful translation of the genetic code and the proper regulation of its activity are necessary for normal cell growth and development. Ribosome assembly is a complex, dynamic process and mechanisms must exist that ensure the correct assembly of ribosomes in order to maintain the fidelity of translation. In addition, ribosome biogenesis accounts for a large portion of the energy expenditure of a rapidly dividing cell and must be coordinated with the metabolic needs of a cell. Indeed, the rapid cell growth of many cancers requires up-regulation of ribosome biogenesis. Thus, understanding the mechanisms regulating ribosome biogenesis will provide insight for the development of new tools for controlling cell proliferation in disease states. The delineation of fundamental cellular pathways such as ribosome biogenesis is also necessary for the intelligent development of new drugs that are specific to their intended cellular targets without impinging adversely on other cellular pathways. This proposal is directed at understanding how the large ribosomal subunit in yeast is transported from its site of assembly in the nucleus to its site of function in the cytoplasm and activated for translation. Although we use yeast as a model organism, these pathways are highly conserved and findings from our work will be relevant to understanding these pathways in human cells as well. This proposal will: 1) Identify how the ribosomal protein Rpl25 and the export receptor Arx1 collaborate in nuclear export of the large (60S) ribosomal subunit. 2) Develop an ordered pathway of all the known cytoplasmic maturation events of the 60S subunit. In this work we will examine the role that assembling the ribosome stalk plays in the final maturation steps of the ribosome. 3) Determine if ribosome biogenesis is coupled with translation in controlling the final maturation step of the 60S subunit.
This project delineates essential and fundamental molecular pathways that are conserved throughout eukaryotes. Understanding these pathways and how they are integrated with other cellular pathways will provide the intellectual underpinning for investigators carrying out translational research.
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|Sardana, Richa; Liu, Xin; Granneman, Sander et al. (2015) The DEAH-box helicase Dhr1 dissociates U3 from the pre-rRNA to promote formation of the central pseudoknot. PLoS Biol 13:e1002083|
|Sulima, Sergey O; Gulay, Suna P; Anjos, Margarida et al. (2014) Eukaryotic rpL10 drives ribosomal rotation. Nucleic Acids Res 42:2049-63|
|Sulima, Sergey O; Patchett, Stephanie; Advani, Vivek M et al. (2014) Bypass of the pre-60S ribosomal quality control as a pathway to oncogenesis. Proc Natl Acad Sci U S A 111:5640-5|
|Merwin, Jason R; Bogar, Lucien B; Poggi, Sarah B et al. (2014) Genetic analysis of the ribosome biogenesis factor Ltv1 of Saccharomyces cerevisiae. Genetics 198:1071-85|
|Sardana, Richa; Zhu, Jieyi; Gill, Michael et al. (2014) Physical and functional interaction between the methyltransferase Bud23 and the essential DEAH-box RNA helicase Ecm16. Mol Cell Biol 34:2208-20|
|Sardana, Richa; White, Joshua P; Johnson, Arlen W (2013) The rRNA methyltransferase Bud23 shows functional interaction with components of the SSU processome and RNase MRP. RNA 19:828-40|
|Castle, Christopher D; Sardana, Richa; Dandekar, Varada et al. (2013) Las1 interacts with Grc3 polynucleotide kinase and is required for ribosome synthesis in Saccharomyces cerevisiae. Nucleic Acids Res 41:1135-50|
|Hartl, Tom A; Ni, Julie; Cao, Jian et al. (2013) Regulation of ribosome biogenesis by nucleostemin 3 promotes local and systemic growth in Drosophila. Genetics 194:101-15|
|De Keersmaecker, Kim; Atak, Zeynep Kalender; Li, Ning et al. (2013) Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat Genet 45:186-90|
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