Molecular Basis for the Single-Nucleotide Precision of Primary microRNA Processing

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Microprocessor, composed of DROSHA and its cofactor DGCR8, initiates microRNA(miRNA) biogenesis by processing the primary transcripts of miRNA (pri-miRNAs). Here we investigate the mechanism by which Microprocessor selects the cleavage site with single-nucleotide precision, which is crucial for the specificity and functionality of miRNAs. By testing similar to 40,000 pri-miRNA variants, we find that for some pri-miRNAs the cleavage site is dictated mainly by the mGHG motif embedded in the lower stem region of pri-miRNA. Structural modeling and deep-sequencing-based complementation experiments show that the double-stranded RNA-binding domain (dsRBD) of DROSHA recognizes mGHG to place the catalytic center in the appropriate position. The mGHG motif as well as the mGHG-recognizing residues in DROSHA dsRBD are conserved across eumetazoans, suggesting that this mechanism emerged in an early ancestor of the animal lineage. Our findings provide a basis for the understanding of miRNA biogenesis and rational design of accurate small-RNA-based gene silencing.
Publisher
CELL PRESS
Issue Date
2019-02
Language
English
Article Type
Article
Citation

MOLECULAR CELL, v.73, no.3, pp.505 - +

ISSN
1097-2765
DOI
10.1016/j.molcel.2018.11.005
URI
http://hdl.handle.net/10203/280415
Appears in Collection
BiS-Journal Papers(저널논문)
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