title: A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence.
abstract: MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail-mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)-tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP- and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 3' UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 5' caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions.
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Syed I A
authors.initials: SIA
authors.lastname: Bukhari
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Truesdell
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sooncheol
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Swapna
authors.initials: S
authors.lastname: Kollu
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Classon
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Boukhali
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Esha
authors.initials: E
authors.lastname: Jain
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Mortensen
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yanagiya
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Sadreyev
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: vasudevan.shobha@mgh.harvard.edu.
authors.forename: Shobha
authors.initials: S
authors.lastname: Vasudevan
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D016922:Cellular Senescence; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D014176:Protein Biosynthesis; D040901:Proteomics / Q000379:methods; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D020413:3' Untranslated Regions; D060565:Argonaute Proteins; D039603:Eukaryotic Initiation Factor-4G; D005095:Exoribonucleases; D035683:MicroRNAs; D012315:RNA Caps; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D012261:Ribonucleoproteins; D058570:TOR Serine-Threonine Kinases; C466422:AGO2 protein, human; C491300:EIF4G2 protein, human; C096916:FXR1 protein, human; C488448:PAIP2 protein, human; C546842:MTOR protein, human