title: Argonaute 2-dependent Regulation of Gene Expression by Single-stranded miRNA Mimics.
abstract: MicroRNAs (miRNAs) are small noncoding transcripts that regulate gene expression. Aberrant expression of miRNAs can affect development of cancer and other diseases. Synthetic miRNA mimics can modulate gene expression and offer an approach to therapy. Inside cells, mature miRNAs are produced as double-stranded RNAs and miRNA mimics typically retain both strands. This need for two strands has the potential to complicate drug development. Recently, synthetic chemically modified single-stranded silencing RNAs (ss-siRNA) have been shown to function through the RNAi pathway to induce gene silencing in cell culture and animals. Here, we test the hypothesis that single-stranded miRNA (ss-miRNA) can also mimic the function of miRNAs. We show that ss-miRNAs can act as miRNA mimics to silence the expression of target genes. Gene silencing requires expression of argonaute 2 (AGO2) protein and involves recruitment of AGO2 to the target transcripts. Chemically modified ss-miRNAs function effectively inside cells through endogenous RNAi pathways and broaden the options for miRNA-based oligonucleotide drug development.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Department of Medicinal Chemistry, Ionis Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Corey
mesh_terms: D000072283:A549 Cells; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D035683:MicroRNAs / Q000138:chemical synthesis / Q000235:genetics*; D018716:Molecular Mimicry
chemical_list: D060565:Argonaute Proteins; D035683:MicroRNAs