Structural differences between pri-miRNA paralogs promotes alternative Drosha cleavage and expands target repertoires

Xavier Bofill De Ros, Wojciech K. Kasprzak, Yuba Bhandari, Lixin Fan, Quinn Cavanaugh, Minjie Jiang, Lisheng Dai, Acong Yang, Tie Juan Shao, Bruce A. Shapiro, Yun Xing Wang, Shuo Gu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jul 10 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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