Oncogenic Biogenesis of pri-miR-17∼92 Reveals Hierarchy and Competition among Polycistronic MicroRNAs

Ariel O. Donayo, Radia M. Johnson, Hsin Wei Tseng, Said Izreig, Alexandra Gariepy, Vinay K. Mayya, Edlyn Wu, Roshni Alam, Carine Lussier, Russell G. Jones, Thomas F. Duchaine

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The microRNAs encoded by the miR-17∼92 polycistron are commonly overexpressed in cancer and orchestrate a wide range of oncogenic functions. Here, we identify a mechanism for miR-17∼92 oncogenic function through the disruption of endogenous microRNA (miRNA) processing. We show that, upon oncogenic overexpression of the miR-17∼92 primary transcript (pri-miR-17∼92), the microprocessor complex remains associated with partially processed intermediates that aberrantly accumulate. These intermediates reflect a series of hierarchical and conserved steps in the early processing of the pri-miR-17∼92 transcript. Encumbrance of the microprocessor by miR-17∼92 intermediates leads to the broad but selective downregulation of co-expressed polycistronic miRNAs, including miRNAs derived from tumor-suppressive miR-34b/c and from the Dlk1-Dio3 polycistrons. We propose that the identified steps of polycistronic miR-17∼92 biogenesis contribute to the oncogenic re-wiring of gene regulation networks. Our results reveal previously unappreciated functional paradigms for polycistronic miRNAs in cancer.

Original languageEnglish
Pages (from-to)340-356.e10
JournalMolecular Cell
Volume75
Issue number2
DOIs
StatePublished - 25 Jul 2019
Externally publishedYes

Keywords

  • 13q31
  • DGCR8
  • Dlk1-Dio3
  • Drosha
  • Eμ myc lymphoma
  • miR-17∼92
  • miR-19
  • microRNA
  • microRNA polycistron
  • microprocessor
  • primary miRNA transcript

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