Abstract

Dicer is a nuclease involved in processing double-stranded RNA (dsRNA) into small RNAs called siRNA and miRNA. These small RNAs are involved in regulating the expression of numerous genes, in diverse organisms, including humans. The proposal will focus on aspects of Dicer that are largely undefined, such as the function of its helicase domain and its role in silencing by endogenous siRNA (endo-siRNA). Mutations will be introduced into the helicase domain of Dicer, and effects monitored in vivo using the model organism C. elegans, and in vitro using biochemical techniques. The hypothesis that Dicer's helicase domain allows it to function processively will be tested. The laboratory's recent results indicate animals with mutations in the helicase domain are devoid of certain endo-siRNA and accumulate their precursors. The latter will allow the first characterization of endo-siRNA precursors. The proposed research will advance our understanding of Dicer, an enzyme that is absolutely essential for life.

Public Health Relevance

Dicer is an enzyme involved in processing small RNAs (miRNA and siRNA), and is essential for human life. The proposed research focuses on the function of Dicer's helicase domain, which is highly conserved between human and C. elegans. The proposed research will enhance our understanding of disease that is based in small RNAs, and provide information important to harnessing their functions in the design of therapies

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM067106-05A2
Application #
7728570
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
2003-02-01
Project End
2011-08-31
Budget Start
2009-09-29
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$396,813
Indirect Cost

  Institution

Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Welker, Noah C; Maity, Tuhin S; Ye, Xuecheng et al. (2011) Dicer's helicase domain discriminates dsRNA termini to promote an altered reaction mode. Mol Cell 41:589-99
Warf, M Bryan; Johnson, W Evan; Bass, Brenda L (2011) Improved annotation of C. elegans microRNAs by deep sequencing reveals structures associated with processing by Drosha and Dicer. RNA 17:563-77
Evan Johnson, W; Welker, Noah C; Bass, Brenda L (2011) Dynamic linear model for the identification of miRNAs in next-generation sequencing data. Biometrics 67:1206-14
Aruscavage, P Joseph; Hellwig, Sabine; Bass, Brenda L (2010) Small DNA pieces in C. elegans are intermediates of DNA fragmentation during apoptosis. PLoS One 5:e11217
Welker, Noah C; Pavelec, Derek M; Nix, David A et al. (2010) Dicer's helicase domain is required for accumulation of some, but not all, C. elegans endogenous siRNAs. RNA 16:893-903
Habig, Jeffrey W; Aruscavage, P Joseph; Bass, Brenda L (2008) In C. elegans, high levels of dsRNA allow RNAi in the absence of RDE-4. PLoS One 3:e4052
Parker, Greg S; Maity, Tuhin Subhra; Bass, Brenda L (2008) dsRNA binding properties of RDE-4 and TRBP reflect their distinct roles in RNAi. J Mol Biol 384:967-79
Habig, Jeffrey W; Dale, Taraka; Bass, Brenda L (2007) miRNA editing--we should have inosine this coming. Mol Cell 25:792-3
Welker, Noah C; Habig, Jeffrey W; Bass, Brenda L (2007) Genes misregulated in C. elegans deficient in Dicer, RDE-4, or RDE-1 are enriched for innate immunity genes. RNA 13:1090-102
Bass, B L (2006) How does RNA editing affect dsRNA-mediated gene silencing? Cold Spring Harb Symp Quant Biol 71:285-92

Showing the most recent 10 out of 11 publications