title: Reduced expression of ribosomal proteins relieves microRNA-mediated repression.
abstract: MicroRNAs (miRNAs) regulate physiological and pathological processes by inducing posttranscriptional repression of target messenger RNAs (mRNAs) via incompletely understood mechanisms. To discover factors required for human miRNA activity, we performed an RNAi screen using a reporter cell line of miRNA-mediated repression of translation initiation. We report that reduced expression of ribosomal protein genes (RPGs) dissociated miRNA complexes from target mRNAs, leading to increased polysome association, translation, and stability of miRNA-targeted mRNAs relative to untargeted mRNAs. RNA sequencing of polysomes indicated substantial overlap in sets of genes exhibiting increased or decreased polysomal association after Argonaute or RPG knockdowns, suggesting similarity in affected pathways. miRNA profiling of monosomes and polysomes demonstrated that miRNAs cosediment with ribosomes. RPG knockdowns decreased miRNAs in monosomes and increased their target mRNAs in polysomes. Our data show that most miRNAs repress translation and that the levels of RPGs modulate miRNA-mediated repression of translation initiation.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maja M
authors.initials: MM
authors.lastname: Janas
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.forename: Tara
authors.initials: T
authors.lastname: Love
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Harris
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Semmelmann
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Shaffer
authors.forename: Po-Hao
authors.initials: PH
authors.lastname: Chen
authors.forename: John G
authors.initials: JG
authors.lastname: Doench
authors.forename: Subrahmanyam V B K
authors.initials: SV
authors.lastname: Yerramilli
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: David E
authors.initials: DE
authors.lastname: Housman
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Burge
authors.forename: Carl D
authors.initials: CD
authors.lastname: Novina
mesh_terms: D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D010442:Peptide Chain Initiation, Translational / Q000235:genetics*; D034622:RNA Interference; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53