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)

[thumbnail of 10.1101.2024.05.09.593372.pdf]
Preview
PDF
10.1101.2024.05.09.593372.pdf - Submitted Version
Available under License Creative Commons Attribution.

Download (8MB) | Preview

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:
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:
URI: https://repository.cshl.edu/id/eprint/41548

Actions (login required)

Administrator's edit/view item Administrator's edit/view item