Post-transcriptional regulation has emerged as a potent way to control quantitatively and qualitatively gene expression. The RNase III family of double-stranded RNA endonucleases plays crucial functions in multiple gene expression pathways: they participate in the processing of precursors of ribosomal RNA, of small RNAs involved in splicing and rRNA metabolism, and of microRNAs. They also participate in the production of small interfering RNAs in the RNA interference process. Our long term goals are (i) to exhaustively identify the gene expression pathways controlled by eukaryotic members of the RNase III family of endonucleases, (ii) to understand the mechanisms by which these enzymes bind and cleave dsRNA and (iii) to understand how the activity of these enzymes is integrated in the cell metabolism. Using the S.cerevisiae enzyme Rntlp as a model eukaryotic RNase III enzyme and functional genomics, we will investigate novel gene expression pathways controlled by this enzyme. The functions of Rntlp in the surveillance and regulation of mRNAs encoding iron uptake proteins and for a protein involved in the methionine salvage pathway will be investigated. Novel genomic strategies will be developed to identify additional gene expression pathways regulated by eukaryotic RNases III. The recognition of double-stranded RNA and the mechanism of cleavage site selection by Rnt1p will be studied using site directed mutagenesis and site-specific modifications of the RNA substrate. The integration of RNase III activity in the cellular context will be investigated. In particular, we will decipher the mechanism by which RNase III is recruited cotranscriptionally to its substrates, and the mechanism by which RNase III is down-regulated in low iron conditions. These studies will contribute to our understanding of the roles of RNase III in the control of gene expression and of the mechanisms of adaptation of eukaryotic cell metabolism to iron deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM061518-08S1
Application #
7486534
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Rhoades, Marcus M
Project Start
2000-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
8
Fiscal Year
2007
Total Cost
$62,054
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gillespie, Abby; Gabunilas, Jason; Jen, Joanna C et al. (2017) Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae. RNA 23:466-472
Gabunilas, Jason; Chanfreau, Guillaume (2016) Splicing-Mediated Autoregulation Modulates Rpl22p Expression in Saccharomyces cerevisiae. PLoS Genet 12:e1005999
Roy, Kevin; Gabunilas, Jason; Gillespie, Abigail et al. (2016) Common genomic elements promote transcriptional and DNA replication roadblocks. Genome Res 26:1363-1375
Hodko, Domagoj; Ward, Taylor; Chanfreau, Guillaume (2016) The Rtr1p CTD phosphatase autoregulates its mRNA through a degradation pathway involving the REX exonucleases. RNA 22:559-70
Al-Hadid, Qais; Roy, Kevin; Chanfreau, Guillaume et al. (2016) Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity. RNA 22:489-98
Chanfreau, Guillaume (2015) Two degrading decades for RNA. RNA 21:584-5
Al-Hadid, Qais; Roy, Kevin; Munroe, William et al. (2014) Histidine methylation of yeast ribosomal protein Rpl3p is required for proper 60S subunit assembly. Mol Cell Biol 34:2903-16
Kawashima, Tadashi; Douglass, Stephen; Gabunilas, Jason et al. (2014) Widespread use of non-productive alternative splice sites in Saccharomyces cerevisiae. PLoS Genet 10:e1004249
Dzialo, Maria C; Travaglini, Kyle J; Shen, Sean et al. (2014) Translational roles of elongation factor 2 protein lysine methylation. J Biol Chem 289:30511-24
Roy, Kevin; Chanfreau, Guillaume (2014) Stress-induced nuclear RNA degradation pathways regulate yeast bromodomain factor 2 to promote cell survival. PLoS Genet 10:e1004661

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