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Structure paper

TitleDICER cleavage fidelity is governed by 5'-end binding pockets.
Journal, issue, pagesNature, Year 2026
Publish dateMar 4, 2026
AuthorsMinh Khoa Ngo / Cong Truc Le / Tuan Anh Nguyen /
PubMed AbstractRNA interference (RNAi) depends on DICER, an essential enzyme that processes RNA precursors into small regulatory RNAs. DICER cleaves RNA precursors according to the 5'-end counting rule, in which ...RNA interference (RNAi) depends on DICER, an essential enzyme that processes RNA precursors into small regulatory RNAs. DICER cleaves RNA precursors according to the 5'-end counting rule, in which RNA length is measured from the 5'-end. Previous work proposed a single 5'-end binding pocket that disfavours guanosine (5'-G), leading to cleavage inaccuracies. Here we show that 5'-G promotes precise cleavage for many substrates. Using massively parallel dicing assays and cryo-electron microscopy, we identify a conserved guanosine-favoured (G-favoured) binding pocket in DICER, distinct from the previously described uridine-favoured (U-favoured) pocket. Together, these pockets influence the alignment between 21-nucleotide and 22-nucleotide cleavage registers, expanding the mechanism of small-RNA biogenesis in metazoan DICERs. We also find that conflicts between 5'-end binding and RNA-motif recognition can trigger RNA conformational adjustments that preserve accurate cleavage-site selection. In addition, conformational adjustments of the double-stranded RNA-binding domain (dsRBD) and PAZ domain help to align substrates with the catalytic centres for precise double-strand cleavage. These results show that the DICER cleavage mechanism integrates dual 5'-end binding pockets, RNA-motif influence and domain motions, advancing our understanding of microRNA biogenesis.
External linksNature / PubMed:41781616
MethodsEM (single particle)
Resolution3.0 - 3.37 Å
Structure data

EMDB-64764, PDB-9v42:
Cryo-EM structure of DICER/26S-GU complex in dicing state
Method: EM (single particle) / Resolution: 3.37 Å

EMDB-64765, PDB-9v43:
Cryo-EM structure of DICER/26S-UG complex in dicing state
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-67570, PDB-21cb:
Cryo-EM structure of DICER with pre-mir-517a-GU in pre-dicing state
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-67573, PDB-21cn:
Cryo-EM structure of DICER with pre-mir-517a-GU in dicing state
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-67575, PDB-21cq:
Cryo-EM structure of DICER-D991G-H992G/26S-GU complex in dicing state
Method: EM (single particle) / Resolution: 3.29 Å

Chemicals

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsHYDROLASE/RNA / Endoribonuclease Dicer / RNA / miRNA / precursor miRNA / HYDROLASE / HYDROLASE-RNA complex / endonuclease / dicer

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