Sci. STKE, 7 September 2004
GENETICS Slicer Steps into the Limelight
During RNA interference, small interfering RNAs (siRNAs) generated by Dicer (or provided exogenously) are loaded onto the RNA-induced silencing complex (RISC), which then binds homologous target RNAs, cleaving and inactivating them. The major constituents of RISC are the single-stranded siRNA and any one of a number of different proteins of the Argonaute (Ago) family. Until now, the identity of the nuclease in RISC, nicknamed "Slicer," has remained a mystery (see the Perspective by Sontheimer and Carthew). Song et al. present the structure of the Ago protein from Pyrococcus furiosus, which consists of four domains; the PAZ and PIWI domains being the defining characteristics of Ago. The PfAgo PIWI domain is homologous to ribonuclease H (RNase H), including conserved catalytic residues, and the juxtaposition of PAZ and PIWI domains suggests a mechanism by which Ago might load and cleave target RNAs. Liu et al. show that, unlike other mouse Agos, only Ago2 can form a cleavage-competent RISC. Ago2 is also essential in vivo for RNAi, and is required for normal mouse development. Because the conserved catalytic residues in the RNase H-like PIWI domain are critical for RISC cleavage activity, it is likely that Ago2 is "Slicer."
J. Liu, M. A. Carmell, F. V. Rivas, C. G. Marsden, J. M. Thomson, J. J. Song, S. M. Hammond, L. Joshua-Tor, G. J. Hannon, Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437-1441 (2004). [Abstract] [Full Text]
Citation: Slicer Steps into the Limelight. Sci. STKE 2004, tw320 (2004).
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