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Mol Cell. 2016 Mar 3;61(5):760-773. doi: 10.1016/j.molcel.2016.02.013.

A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence.

Author information

1
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.
2
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
3
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
4
Department of Biochemistry, Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
5
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.
6
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.

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.

PMID:
26942679
PMCID:
PMC4811377
[Available on 2017-03-03]
DOI:
10.1016/j.molcel.2016.02.013
[Indexed for MEDLINE]
Free PMC Article

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