1. Small-RNA asymmetry is directly driven by mammalian Argonautes.
- Author
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Suzuki, Hiroshi I, Katsura, Akihiro, Yasuda, Takahiko, Ueno, Toshihide, Mano, Hiroyuki, Sugimoto, Koichi, and Miyazono, Kohei
- Subjects
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NON-coding RNA , *DOUBLE-stranded RNA , *GENETIC regulation , *MAMMAL genetics , *ADENOSINES , *BASE pairs - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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