Ago2-dependent processing allows miR-451 to evade the global microRNA turnover elicited during erythropoiesis

Dmitry Kretov, Walawalkar Isha, Alexandra Mora-Martin, Andrew Shafik, Simon Moxon, Daniel Cifuentes

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MicroRNAs (miRNAs) are sequentially processed by two RNase III enzymes, Drosha and Dicer. miR-451 is the only known miRNA whose processing bypasses Dicer and instead relies on the slicer activity of Argonaute-2 (Ago2). miR-451 is highly conserved in vertebrates and regulates erythrocyte maturation, where it becomes the most abundant miRNA. However, the basis for the non-canonical biogenesis of miR-451 is unclear. Here, we show that Ago2 is less efficient than Dicer in processing pre-miRNAs, but this deficit is overcome when miR-144 represses Dicer in a negative-feedback loop during erythropoiesis. Loss of miR-144-mediated Dicer repression in zebrafish embryos and human cells leads to increased canonical miRNA production and impaired miR-451 maturation. Overexpression of Ago2 rescues some of the defects of miR-451 processing. Thus, the evolution of Ago2-dependent processing allows miR-451 to circumvent the global repression of canonical miRNAs elicited, in part, by the miR-144 targeting of Dicer during erythropoiesis.

Original languageEnglish
Pages (from-to)317-328.e6
Number of pages12
JournalMolecular Cell
Issue number2
Early online date18 Mar 2020
Publication statusPublished - 16 Apr 2020


  • Ago2
  • Ago2-dependent
  • Dicer
  • Dicer-independent
  • erythropoiesis
  • miR-144
  • miR-451
  • microRNA
  • non-canonical microRNA
  • zebrafish

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