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Mechanism of action of miRNA
Author(s) -
Fabian Marc R.,
Sonenberg Nahum
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.461.3
Subject(s) - microbiology and biotechnology , gene silencing , microrna , translation (biology) , messenger rna , rna binding protein , three prime untranslated region , psychological repression , untranslated region , chemistry , p bodies , biology , gene expression , gene , biochemistry
MicroRNAs (miRNAs) inhibit mRNA expression in general by base pairing to the 3′UTR of target mRNAs and consequently inhibiting translation and/or initiating poly(A) tail deadenylation and mRNA destabilization. We established a mouse Krebs‐2 ascites extract that faithfully recapitulates the miRNA action in cells (Mathonnet et al., 2007). We demonstrated that the let‐7 miRNA inhibits translation of reporter mRNA at the initiation step. Translation inhibition is subsequently consolidated by let‐7‐mediated deadenylation, which requires both the poly(A) binding protein (PABP) and the CAF1 deadenylase, which interact with the let‐7 miRNA‐loaded RNA‐induced silencing complex (miRISC) (Fabian et al., 2009). Importantly, we demonstrated that GW182, a core component of the miRISC, directly interacts with PABP via its C‐terminus and that this interaction enhances miRNA‐mediated deadenylation (Fabian et al., 2009; Jinek et al., 2010). The miRISC binds the deadenylation machinery directly and independently of PABP. We are now studying how the miRISC recruits the deadenylation machinery in a PABP‐independent manner, and how these interactions impact both deadenylation‐dependent and – independent translational repression.