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Mol Cell. 2020 Mar 12. pii: S1097-2765(20)30113-1. doi: 10.1016/j.molcel.2020.02.020. [Epub ahead of print]

Ago2-Dependent Processing Allows miR-451 to Evade the Global MicroRNA Turnover Elicited during Erythropoiesis.

Author information

1
Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
2
School of Biological Sciences, University of East Anglia, Norwich, UK.
3
Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA. Electronic address: dcb@bu.edu.

Abstract

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.

KEYWORDS:

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

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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