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Cell Rep. 2019 Jan 8;26(2):447-459.e4. doi: 10.1016/j.celrep.2018.12.054.

Structural Differences between Pri-miRNA Paralogs Promote Alternative Drosha Cleavage and Expand Target Repertoires.

Author information

1
RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
2
Basic Science Program, RNA Biology Laboratory, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA.
3
Protein-Nucleic Acid Interaction Section, Structural Biophysics Laboratory, National Cancer Institute, Frederick, MD 21702, USA.
4
Small-Angle X-ray Scattering Core Facility, Center for Cancer Research of the National Cancer Institute, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
5
RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
6
RNA Structure and Design Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
7
RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: shuo.gu@nih.gov.

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 has a potential role in tumor progression. Furthermore, we provide evidence that distortion of pri-miRNA stems induced by asymmetric internal loops correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.

KEYWORDS:

Drosha; RNA structure; isomiRs; miR-9; microprocessor; paralogs; primary miRNA

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