Abstract
MicroRNAs (miRNAs) regulate gene expression through translation repression and mRNA destabilization. However, the molecular mechanisms of miRNA silencing are still not well defined. Using a genetic screen in mouse embryonic stem (ES) cells, we identify mammalian hyperplastic discs protein EDD, a known E3 ubiquitin ligase, as a key component of the miRNA silencing pathway. ES cells deficient for EDD are defective in miRNA function and exhibit growth defects. We demonstrate that E3 ubiquitin ligase activity is dispensable for EDD function in miRNA silencing. Instead, EDD interacts with GW182 family proteins in the Argonaute-miRNA complexes. The PABC domain of EDD is essential for its silencing function. Through the PABC domain, EDD participates in miRNA silencing by recruiting downstream effectors. Among the PABC-interactors, DDX6 and Tob1/2 are both required and sufficient for silencing mRNA targets. Taken together, these data demonstrate a critical function for EDD in miRNA silencing.
Original language | English (US) |
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Pages (from-to) | 97-109 |
Number of pages | 13 |
Journal | Molecular cell |
Volume | 43 |
Issue number | 1 |
DOIs | |
State | Published - Jul 8 2011 |
Funding
We thank M.J. Henderson and C.K. Watts for human EDD cDNA, E. Izaurralde for various TNRC6A constructs, S. Krobitsch for human ATXN2 cDNA and M. Kiriakidou for anti-Ago (2A8) antibody. This work was supported by grants from NIGMS (5R21GM079528) and NU-PSOC (under 5U45CA143869) to X.W.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology