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Genes Dev. 2016 Sep 15;30(18):2076-2092.

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs.

Burke JM1,2,3,4, Kincaid RP1,2,3,4, Nottingham RM1,2,3, Lambowitz AM1,2,3, Sullivan CS1,2,3,4.

Author information

1
Institute for Cellular and Molecular Biology, College of Natural Sciences, The University of Texas at Austin, Austin, Texas 78712, USA.
2
Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
3
Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, Texas 78712, USA.
4
John Ring LaMontagne Center for Infectious Disease, College of Natural Sciences, The University of Texas at Austin, Austin, Texas 78712, USA.

Abstract

RNA silencing is a conserved eukaryotic gene expression regulatory mechanism mediated by small RNAs. In Caenorhabditis elegans, the accumulation of a distinct class of siRNAs synthesized by an RNA-dependent RNA polymerase (RdRP) requires the PIR-1 phosphatase. However, the function of PIR-1 in RNAi has remained unclear. Since mammals lack an analogous siRNA biogenesis pathway, an RNA silencing role for the mammalian PIR-1 homolog (dual specificity phosphatase 11 [DUSP11]) was unexpected. Here, we show that the RNA triphosphatase activity of DUSP11 promotes the RNA silencing activity of viral microRNAs (miRNAs) derived from RNA polymerase III (RNAP III) transcribed precursors. Our results demonstrate that DUSP11 converts the 5' triphosphate of miRNA precursors to a 5' monophosphate, promoting loading of derivative 5p miRNAs into Argonaute proteins via a Dicer-coupled 5' monophosphate-dependent strand selection mechanism. This mechanistic insight supports a likely shared function for PIR-1 in C. elegans Furthermore, we show that DUSP11 modulates the 5' end phosphate group and/or steady-state level of several host RNAP III transcripts, including vault RNAs and Alu transcripts. This study shows that steady-state levels of select noncoding RNAs are regulated by DUSP11 and defines a previously unknown portal for small RNA-mediated silencing in mammals, revealing that DUSP11-dependent RNA silencing activities are shared among diverse metazoans.

KEYWORDS:

Alu; BLV; DUSP11; RNAi; adenovirus; vault RNA

PMID:
27798849
PMCID:
PMC5066614
DOI:
10.1101/gad.282616.116
[Indexed for MEDLINE]
Free PMC Article
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