Structural Differences Between Pri-miRNA Paralogs Promotes Alternative Drosha Cleavage and Expands Target Repertoires

Authors

• X Bofill-De Ros
• WK Kasprzak
• Y Bhandari
• L Fan
• Q Cavanaugh
• M Jiang
• L Dai
• A Yang
• TJ Shao
• BA Shapiro
• YX Wang
• S Gu

Abstract

MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative-miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low grade glioma patient samples indicate that the alternative-miR-9 plays a distinct role in preventing tumor progression. To generalize our model, we provide evidence that distortion of pri-miRNA stems correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.

Scientific Focus Area: Genetics and Genomics

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