Stress-induced Reversal of MicroRNA Repression and mRNA P-body Localization in Human Cells

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Abstract
In metazoa, microRNAs (miRNAs) imperfectly base-pair with the 3'-untranslated region (3'UTR) of mRNAs and preventprotein accumulation by either repressing translation or inducing mRNA degradation. Examples of specific mRNAs undergoingmiRNA-mediated repression are numerous, but whether the repression is a reversible process remains largelyunknown. Here, we show that cationic amino acid transporter 1 (CAT-1) mRNA and reporters bearing the CAT-1 3'UTRor its fragments can be relieved from the miRNA miR-122-induced inhibition in human hepatoma cells in response todifferent stress conditions. The derepression of CAT-1 mRNA is accompanied by its release from cytoplasmic processingbodies (P bodies) and its recruitment to polysomes, indicating that P bodies act as storage sites for mRNAs inhibited bymiRNAs. The derepression requires binding of HuR, an AU-rich-element-binding ELAV family protein, to the 3'UTR ofCAT-1 mRNA. We propose that proteins interacting with the 3'UTR will generally act as modifiers altering the potentialof miRNAs to repress gene expression.