Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 20, Issue 6, Pages 662-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2564
Keywords
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Funding
- US National Science Foundation (NSF) Graduate Research Fellow
- NSF
- Japan Society for the Promotion of Science East Asia and Pacific Summer Institute Fellow
- US National Institutes of Health (NIH) [5 T32 GM008283]
- Core Research for Evolutional Science and Technology of Japan Science and Technology Agency
- NIH [5R01GM073794]
- Human Frontiers in Science Program [RPG0039/2008-C]
- Smith Family Awards Program for Excellence in Biomedical Research
- National Natural Science Foundation of China [31270765]
- Howard Hughes Medical Institute Investigators
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Dicer has a central role in RNA-interference pathways by cleaving double-stranded RNAs (dsRNAs) to produce small regulatory RNAs. Human Dicer can process long double-stranded and hairpin precursor RNAs to yield short interfering RNAs (siRNAs) and microRNAs (miRNAs), respectively. Previous studies have shown that pre-miRNAs are cleaved more rapidly than pre-siRNAs in vitro and are the predominant natural Dicer substrates. We have used EM and single-particle analysis of Dicer-RNA complexes to gain insight into the structural basis for human Dicer's substrate preference. Our studies show that Dicer traps pre-siRNAs in a nonproductive conformation, whereas interactions of Dicer with pre-miRNAs and dsRNA-binding proteins induce structural changes in the enzyme that enable productive substrate recognition in the central catalytic channel. These findings implicate RNA structure and cofactors in determining substrate recognition and processing efficiency by human Dicer.
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