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bioRxiv · 10.1101/2024.05.09.593372

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

Garg, A.·Shang, R.·Cvetanovic, T.·Lai, E. C.·Joshua-Tor, L.
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Abstract

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 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 "fUN" motif. Our analysis explains how cleavage of class-II pri-let-7 members harboring a bulged nucleotide generates a noncanonical 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 Droshas 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.

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Garg, A., Shang, R., Cvetanovic, T., Lai, E. C., Joshua-Tor, L.. 2024-05-09. The structural landscape of Microprocessor Mediated pri-let-7 miRNAs processing. https://doi.org/10.1101/2024.05.09.593372

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