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Fig. 2 MiRNAs are often found in clusters embedded into introns of protein coding genes or noncoding tran-
scription units. MiRNAs are transcribed by RNA polymerase II (Pol II) as long primary miRNA (pri-MiRNA) tran-
scripts. The microprocessor composed of the RNAse III-like enzyme Drosha and its partner dsRNA-binding
protein DGCR8 (DiGeorge syndrome critical region gene 8, also known as Pasha in Drosophila or C . elegans )
cut miRNA hairpins from pre-miRNA producing pre-miRNA. Pre-miRNA is exported out of the nucleus by a
member of the karyopherin family of nucleocytoplasmic transport receptors Exportin-5. In the cytoplasm, pre-
miRNA is cut by Dicer to remove the terminal loop, which produces miRNA duplex. In the human and, likely,
other vertebrates, Dicer in complex with dsRNA-binding proteins TRBP (the human immunodefi ciency virus
transactivating response RNA-binding protein) and PACT recruits the endonuclease Slicer Argaunate-2 (Ago-
2). The latter binds miRNA duplexes and cleaves the passenger chain. In the human, miRNA duplexes might
bind to the preformed Dicer-TRBP-Ago-2 complex. The Dicer-TRBP-PAC complex is sometimes referred to
as RISC-loading complex (RLC) by analogy to a similar complex in Drosophila. RISC, or RNA-induced silencing
complex, is the effector complex for the miRNA pathway that mediates mRNA degradation of translation
repression of the target genes guided by the miRNA guide strand (mature miRNA). The Dicer-TRBP-PAC-
Ago-2 complex is often known as pre-RISC or simply RISC. The current understanding is that when the pas-
senger strand is destroyed, Dicer-TRBP-PAC dissociate, and Ago-2 with bound mature miRNA constitutes
mature RISC or holo-RISC. Also note that although the overall miRNA pathway is remarkably conserved, the
details differ between species. The description above applies to mechanisms elucidated in human cells. The
details of the RISC formation in different species still remain to be worked out
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