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Mol Cell. 2014 Sep 18;55(6):868-879. doi: 10.1016/j.molcel.2014.07.017. Epub 2014 Aug 28.

A MicroRNA precursor surveillance system in quality control of MicroRNA synthesis.

Author information

1
Department of Pathology and Laboratory Medicine, Division of Neuropathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Pathology and Laboratory Medicine, Division of Neuropathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: mourelaz@uphs.upenn.edu.

Abstract

MicroRNAs (miRNAs) are essential for regulation of gene expression. Though numerous miRNAs have been identified by high-throughput sequencing, few precursor miRNAs (pre-miRNAs) are experimentally validated. Here we report a strategy for constructing high-throughput sequencing libraries enriched for full-length pre-miRNAs. We find widespread and extensive uridylation of Argonaute (Ago)-bound pre-miRNAs, which is primarily catalyzed by two terminal uridylyltransferases: TUT7 and TUT4. Uridylation by TUT7/4 not only polishes pre-miRNA 3' ends, but also facilitates their degradation by the exosome, preventing clogging of Ago with defective species. We show that the exosome exploits distinct substrate preferences of DIS3 and RRP6, its two catalytic subunits, to distinguish productive from defective pre-miRNAs. Furthermore, we identify a positive feedback loop formed by the exosome and TUT7/4 in triggering uridylation and degradation of Ago-bound pre-miRNAs. Our study reveals a pre-miRNA surveillance system that comprises TUT7, TUT4, and the exosome in quality control of miRNA synthesis.

PMID:
25175028
PMCID:
PMC4169771
DOI:
10.1016/j.molcel.2014.07.017
[Indexed for MEDLINE]
Free PMC Article

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