The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs Journal Article
| Authors: | Garg, A.; Shang, R.; Cvetanovic, T.; Lai, E. C.; Joshua-Tor, L. |
| Article Title: | The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs |
| Abstract: | MicroRNA (miRNA) biogenesis is initiated upon cleavage of a primary miRNA (pri-miRNA) hairpin by the 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 cryoelectron microscopy (cryo-EM) and biochemical studies of several let-7 family pri-miRNAs in complex with human MP. We show that MP has the structural plasticity to accommodate a range of pri-miRNAs. These structures revealed key features of the 5′ UG sequence motif, more comprehensively represented as the “flipped U with paired N (fUN)” motif. Our analysis explains how cleavage of class-II pri-let-7 members harboring a bulged nucleotide generates a non-canonical precursor with a 1-nt 3′ overhang. Finally, the MP-SRSF3-pri-let-7f1 structure reveals how SRSF3 contributes to MP fidelity by interacting with the CNNC motif and Drosha's PAZ-like domain. Overall, this study sheds light on the mechanisms for flexible recognition, accurate cleavage, and regulated processing of different pri-miRNAs by MP. © 2024 The Author(s) |
| Keywords: | human cell; genetics; protein motif; metabolism; microrna; protein binding; rna binding protein; rna-binding proteins; chemistry; conformation; nucleic acid conformation; micrornas; rna processing; biogenesis; ribonuclease iii; rna processing, post-transcriptional; cryoelectron microscopy; rnai; hek293 cells; cryo-em; microprocessor; mirna biogenesis; humans; human; article; hek293 cell line; protein-rna; dgcr8 protein, human; drosha protein, human; mirnlet7 microrna, human |
| Journal Title: | Molecular Cell |
| Volume: | 84 |
| Issue: | 21 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2024-11-07 |
| Start Page: | 4175 |
| End Page: | 4190.e6 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2024.09.008 |
| PUBMED: | 39368465 |
| PROVIDER: | scopus |
| PMCID: | PMC11560618 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work