title: Small-RNA asymmetry is directly driven by mammalian Argonautes.
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.
authors.affiliation: 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.
authors.forename: Hiroshi I
authors.initials: HI
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katsura
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.affiliation: Department of Hematology and Oncology, JR Tokyo General Hospital, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D035683:MicroRNAs