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A dicer-independent miRNA biogenesis pathway that requires Ago catalysis

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  • Sihem Cheloufi

    (Cold Spring Harbor Laboratory, Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA
    Graduate Program in Genetics, Stony Brook University, Stony Brook, New York 11794, USA)

  • Camila O. Dos Santos

    (Cold Spring Harbor Laboratory, Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA)

  • Mark M. W. Chong

    (The Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA
    The Walter and Eliza Hall Institute of Medical Research Parkville)

  • Gregory J. Hannon

    (Cold Spring Harbor Laboratory, Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA)

Abstract

The nucleolytic activity of animal Argonaute proteins is deeply conserved, despite its having no obvious role in microRNA-directed gene regulation. In mice, Ago2 (also known as Eif2c2) is uniquely required for viability, and only this family member retains catalytic competence. To investigate the evolutionary pressure to conserve Argonaute enzymatic activity, we engineered a mouse with catalytically inactive Ago2 alleles. Homozygous mutants died shortly after birth with an obvious anaemia. Examination of microRNAs and their potential targets revealed a loss of miR-451, a small RNA important for erythropoiesis. Though this microRNA is processed by Drosha (also known as Rnasen), its maturation does not require Dicer. Instead, the pre-miRNA becomes loaded into Ago and is cleaved by the Ago catalytic centre to generate an intermediate 3′ end, which is then further trimmed. Our findings link the conservation of Argonaute catalysis to a conserved mechanism of microRNA biogenesis that is important for vertebrate development.

Suggested Citation

  • Sihem Cheloufi & Camila O. Dos Santos & Mark M. W. Chong & Gregory J. Hannon, 2010. "A dicer-independent miRNA biogenesis pathway that requires Ago catalysis," Nature, Nature, vol. 465(7298), pages 584-589, June.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7298:d:10.1038_nature09092
    DOI: 10.1038/nature09092
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    Cited by:

    1. Justine M Pompey & Bardees Foda & Upinder Singh, 2015. "A Single RNaseIII Domain Protein from Entamoeba histolytica Has dsRNA Cleavage Activity and Can Help Mediate RNAi Gene Silencing in a Heterologous System," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-21, July.

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