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

Author:

Bofill De Ros, Xavier

Kasprzak, Wojciech

Bhandari, Yuba

Fan, Lixin

Cavanaugh, Quinn

Jiang, Minjie

Dai, Lisheng

Yang, Acong

Shao, Tie-Juan

Shapiro, Bruce

Wang, Yun-Xing

Gu, Shuo
Author Address

RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Basic Science Program, RNA Biology Laboratory, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA., Protein-Nucleic Acid Interaction Section, Structural Biophysics Laboratory, National Cancer Institute, Frederick, MD 21702, USA., 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., 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., RNA Structure and Design Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., 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. Published by Elsevier Inc.

See More

Author Address