Argonaute 2 (Ago2) is unique among its family: It is the only one of the four mammalian Argonaute proteins that exhibits endonuclease 'slicer' activity (facilitation of miRNA-guided cleavage of target mRNA).
However, as Drs. Donal O'Carroll and Alexander Tarakhovsky (The Rockefeller Institute) report in an upcoming issue of G&D, Ago2's defining characteristic is surprisingly non-essential for its role in hematopoiesis and miRNA biogenesis.
An advanced version of their paper will be posted online at www.genesdev.org
Drs. O'Carroll, Tarakhovsky and colleagues generated transgenic mice harboring mutated versions of Ago2 in their bone marrow. The researchers found that Ago2 is, indeed, quite necessary for normal blood cell development. Its endonulcease activity, however, is not.
The scientists were able to restore erythropoiesis in Ago2-deficient mice by expressing a mutated version of Ago2 that lacks its endonuclease activity, thereby demonstrating that the role of Ago2 in the hematopoietic system is independent of its slicer activity. Rather, Dr. O'Carroll and colleagues found that Ago2 regulates miRNA biogenesis in blood cells.
"Our results suggest that the effector function of miRNA in somatic cells relies mostly on translational control of gene expression rather than on destruction of the mRNA targets. This finding may force rethinking of current strategies for the identification of miRNA targets in cells with individual miRNA overexpression or deficiency," explains Dr. Tarakhovsky.