Dual Role for Argonautes in MicroRNA Processing and Posttranscriptional Regulation of MicroRNA Expression

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Cell (Impact Factor: 33.12). 01/2008; 131(6):1097-108. DOI: 10.1016/j.cell.2007.10.032
Source: PubMed

ABSTRACT MicroRNAs are small endogenous noncoding RNAs involved in posttranscriptional gene regulation. During microRNA biogenesis, Drosha and Dicer process the primary transcript (pri-miRNA) through a precursor hairpin (pre-miRNA) to the mature miRNA. The miRNA is incorporated into the RNA-Induced Silencing Complex (RISC) with Argonaute proteins, the effector molecules in RNA interference (RNAi). Here, we show that all Argonautes elevate mature miRNA expression posttranscriptionally, independent of RNase activity. Also, we identify a role for the RISC slicer Argonaute2 (Ago2) in cleaving the pre-miRNA to an additional processing intermediate, termed Ago2-cleaved precursor miRNA or ac-pre-miRNA. This endogenous, on-pathway intermediate results from cleavage of the pre-miRNA hairpin 12 nucleotides from its 3'-end. By analogy to siRNA processing, Ago2 cleavage may facilitate removal of the nicked passenger strand from RISC after maturation. The multiple roles of Argonautes in the RNAi effector phase and miRNA biogenesis and maturation suggest coordinate regulation of microRNA expression and function.

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Available from: Sven Diederichs, Jan 09, 2014
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    • "Consistent with these changes, increased expression of components of the miRNA processing pathway has been detected in the brains of schizophrenic patients (Beveridge et al., 2010; Santarelli et al., 2011). Additionally, the expression of Ago2, which is involved in effecting miRNA-induced silencing (Cenik and Zamore, 2011), as well as the regulation of mature miRNA expression and miRNA processing (Diederichs and Haber, 2007), has been found to be down-regulated in peripheral blood mononuclear cells in schizophrenic patients (Gardiner et al., 2013). miRNAs are short (~22 nt) RNA sequences that can each target hundreds of mRNAs by complementarity to the 3 0 untranslated region, generally resulting in the suppression of gene expression either by affecting mRNA stability or translation (Valencia-Sanchez et al., 2006). "
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    • "MicroRNAs abundance is dependent on the presence of Argonaute proteins. It has been previously reported that a loss of Ago2 resulted in loss of microRNA and the reexpression of Argonaute proteins led to increased expression of precursor microRNAs [8]. However, the mechanisms that regulate microRNAs turnover are not fully understood neither perhaps fully identified. "
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