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Nat Struct Mol Biol. 2015 Jul;22(7):512-21. doi: 10.1038/nsmb.3050. Epub 2015 Jun 22.

Small-RNA asymmetry is directly driven by mammalian Argonautes.

Author information

1
1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
3
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
4
Department of Hematology and Oncology, JR Tokyo General Hospital, Tokyo, Japan.

Abstract

Asymmetric selection of single-stranded guide RNAs from double-stranded RNA precursors is crucial in RNA silencing-mediated gene regulation. However, the precise mechanisms of small-RNA asymmetry are unclear, especially because asymmetric selection can still occur when the putative asymmetry sensors Drosophila R2D2 and mammalian Dicer are depleted. Here we report a direct contribution of mammalian Argonaute 2 (Ago2) to microRNA (miRNA) asymmetry. Ago2 selects strands with 5'-uridine or 5'-adenosine and thermodynamically unstable 5' ends in parallel through its two sensor regions, which contact the 5' nucleobases and 5'-phosphates of prospective guide strands. Hence, miRNA asymmetry shows superposed patterns reflecting 5'-end nucleotide identity ('digital' pattern) and thermodynamic stability ('analog' pattern). Furthermore, we demonstrate that cancer-associated miRNA variations reprogram asymmetric selection. Finally, our study presents a model of this universal principle, to aid in comprehensive understanding of miRNA function and development of new RNA-silencing therapies in precision medicine.

PMID:
26098316
DOI:
10.1038/nsmb.3050
[Indexed for MEDLINE]

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