The structural landscape of Microprocessor Mediated pri-let-7 miRNAs processing

Garg, Ankur, Shang, Renfu, Cvetanovic, Todor, Lai, Eric C, Joshua-Tor, Leemor (May 2024) The structural landscape of Microprocessor Mediated pri-let-7 miRNAs processing. bioRxiv. (Submitted)

PDF 10.1101.2024.05.09.593372.pdf - Submitted Version Available under License Creative Commons Attribution. Download (8MB)

Abstract

miRNA biogenesis is initiated upon cleavage of a primary miRNA (pri-miRNA) hairpin by Microprocessor (MP), composed of the Drosha RNase III enzyme and its partner DGCR8. Multiple pri-miRNA sequence motifs affect MP recognition, fidelity, and efficiency. Here, we performed cryo-EM and biochemical studies of several let-7 family pri-miRNAs in complex with human MP. We show that MP has structural plasticity to accommodate different pri-miRNAs. These also revealed key structural features of the 5’ UG sequence motif, more comprehensively represented as the “fUN” motif. Our analysis explains how the bulged nucleotide in class-II pri-let-7 members alters Drosha cleavage, generating a noncanonical precursor with 1-nt 3’ overhang. Finally, the MP-SRSF3-pri-let-7f1 structure reveals how SRSF3 interacts with the CNNC motif and Drosha’s PAZ-like domain, to promote proper Drosha loading onto the basal hairpin junction. Overall, our work illuminates the mechanisms for flexible recognition, accurate cleavage, and regulated processing of different pri-miRNAs by MP.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
CSHL Authors:	Garg, Ankur Joshua-Tor, Leemor Cvetanovic, Todor
Communities:	CSHL labs > Joshua-Tor lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	9 May 2024
Date Deposited:	17 May 2024 12:27
Last Modified:	17 May 2024 12:27
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41548

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