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Structure of the human DICER-pre-miRNA complex in a dicing state

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Title
Structure of the human DICER-pre-miRNA complex in a dicing state
Author(s)
Young-Yoon Lee; Lee, Hansol; Haedong Kim; V. Narry Kim; Roh, Soung-Hun
Publication Date
2023-03
Journal
NATURE, v.615, no.7951, pp.331 - 338
Publisher
NATURE PORTFOLIO
Abstract
Dicer has a key role in small RNA biogenesis, processing double-stranded RNAs (dsRNAs)(1,2). Human DICER (hDICER, also known as DICER1) is specialized for cleaving small hairpin structures such as precursor microRNAs (pre-miRNAs) and has limited activity towards long dsRNAs-unlike its homologues in lower eukaryotes and plants, which cleave long dsRNAs. Although the mechanism by which long dsRNAs are cleaved has been well documented, our understanding of pre-miRNA processing is incomplete because structures of hDICER in a catalytic state are lacking. Here we report the cryo-electron microscopy structure of hDICER bound to pre-miRNA in a dicing state and uncover the structural basis of pre-miRNA processing. hDICER undergoes large conformational changes to attain the active state. The helicase domain becomes flexible, which allows the binding of pre-miRNA to the catalytic valley. The double-stranded RNA-binding domain relocates and anchors pre-miRNA in a specific position through both sequence-independent and sequence-specific recognition of the newly identified 'GYM motif'(3). The DICER-specific PAZ helix is also reoriented to accommodate the RNA. Furthermore, our structure identifies a configuration of the 5' end of pre-miRNA inserted into a basic pocket. In this pocket, a group of arginine residues recognize the 5 & PRIME; terminal base (disfavouring guanine) and terminal monophosphate; this explains the specificity of hDICER and how it determines the cleavage site. We identify cancer-associated mutations in the 5' pocket residues that impair miRNA biogenesis. Our study reveals how hDICER recognizes pre-miRNAs with stringent specificity and enables a mechanistic understanding of hDICER-related diseases.
URI
https://pr.ibs.re.kr/handle/8788114/13077
DOI
10.1038/s41586-023-05723-3
ISSN
0028-0836
Appears in Collections:
Center for RNA Research(RNA 연구단) > 1. Journal Papers (저널논문)
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