Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation

TLDR

AU‑rich elements and microRNA target sites in mRNA 3′UTRs regulate post‑transcriptional gene expression, and during cell‑cycle arrest the TNFα ARE becomes a translation‑activation signal recruiting AGO and FXR1. The study proposes that microRNP‑mediated translation regulation oscillates between repression and activation across the cell cycle. The authors demonstrate that miR369‑3, Let‑7, and miRcxcr4 recruit AGO and FXR1 to AREs to activate translation during cell‑cycle arrest, showing that microRNPs commonly up‑regulate translation in arrested cells while repressing it in proliferating cells.

Abstract

AU-rich elements (AREs) and microRNA target sites are conserved sequences in messenger RNA (mRNA) 3′ untranslated regions (3′UTRs) that control gene expression posttranscriptionally. Upon cell cycle arrest, the ARE in tumor necrosis factor–α (TNFα) mRNA is transformed into a translation activation signal, recruiting Argonaute (AGO) and fragile X mental retardation–related protein 1 (FXR1), factors associated with micro-ribonucleoproteins (microRNPs). We show that human microRNA miR369-3 directs association of these proteins with the AREs to activate translation. Furthermore, we document that two well-studied microRNAs—Let-7 and the synthetic microRNA miRcxcr4—likewise induce translation up-regulation of target mRNAs on cell cycle arrest, yet they repress translation in proliferating cells. Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle.