title: Role of pri-miRNA tertiary structure in miR-17~92 miRNA biogenesis.
abstract: MicroRNAs (miRNAs) regulate gene expression in a variety of biological pathways such as development and tumourigenesis. miRNAs are initially expressed as long primary transcripts (pri-miRNAs) that undergo sequential processing by Drosha and then Dicer to yield mature miRNAs. miR-17~92 is a miRNA cluster that encodes 6 miRNAs and while it is essential for development it also has reported oncogenic activity. To date, the role of RNA structure in miRNA biogenesis has only been considered in terms of the secondary structural elements required for processing of pri-miRNAs by Drosha. Here we report that the miR-17~92 cluster has a compact globular tertiary structure where miRNAs internalized within the core of the folded structure are processed less efficiently than miRNAs on the surface of the structure. Increased miR-92 expression resulting from disruption of the compact miR-17~92 structure results in increased repression of integrin α5 mRNA, a known target of miR-92a. In summary, we describe the first example of pri-miRNA structure modulating differential expression of constituent miRNAs.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. schaulk@ualberta.ca
authors.forename: Steven G
authors.initials: SG
authors.lastname: Chaulk
authors.forename: Gina L
authors.initials: GL
authors.lastname: Thede
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Kent
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Xu
authors.forename: Emily M
authors.initials: EM
authors.lastname: Gesner
authors.forename: Richard A
authors.initials: RA
authors.lastname: Veldhoen
authors.forename: Suneil K
authors.initials: SK
authors.lastname: Khanna
authors.forename: Ing Swie
authors.initials: IS
authors.lastname: Goping
authors.forename: Andrew M
authors.initials: AM
authors.lastname: MacMillan
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
authors.forename: Howard S
authors.initials: HS
authors.lastname: Young
authors.forename: Richard P
authors.initials: RP
authors.lastname: Fahlman
authors.forename: J N Mark
authors.initials: JN
authors.lastname: Glover
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics; D035683:MicroRNAs / Q000737:chemistry*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009690:Nucleic Acid Conformation; D059370:RNA Folding; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: D039482:Integrin alpha5; C524941:MIRN17 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C517918:DROSHA protein, human; D043244:Ribonuclease III