The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis

RNA interference (RNAi) is an evolutionarily conserved process through which double-stranded RNA (dsRNA) induces the silencing of cognate genes (for review, see Bernstein et al. 2001b;Carthew 2001). Sources of dsRNA silencing triggers include experimentally introduced dsRNAs, RNA viruses, transposons, and RNAs transcribed from complex transgene arrays (for review, see Hammond et al. 2001b). Short hairpin sequences encoded in the genome also appear to enter the RNAi pathway and function to regulate the expression of endogenous, protein-coding genes (Grishok et al. 2001; Hutvagner et al. 2001; Ketting et al. 2001; Knight and Bass 2001; Hutvagner and Zamore 2002).

According to the current mechanistic model, dsRNAs initiate RNAi following their conversion into small, 21–24-nucleotide (nt) short interfering RNAs (siRNAs; Hamilton and Baulcombe 1999; Zamore et al. 2000; Bernstein et al. 2001a; Elbashir et al. 2001). The siRNAs then guide an effector complex referred to as the RNA-induced silencing complex, or RISC, to its cognate substrates (Hammond et al. 2000;Zamore et al. 2000). Both biochemical and genetic studies have led to the identification of two, conserved gene families that are universal components of the interference process. These are the Dicer family, which is comprised of members of the Ribonuclease III family of enzymes, and the Argonaute gene family, which is comprised of proteins with unknown biochemical function. An examination of the phenotypes arising from mutations in these classes of genes has revealed that RNAi and related pathways may participate in a rich array of biological processes, many of which are, as yet, only tenuously linked to RNAi. The purpose of this review is to draw from studies of the Argonaute gene family to illustrate the potentially conserved impact of RNA interference and related pathways on diverse biological processes.