eEF2K is a kinase that controls the rate of peptide chain elongation by phosphorylating eukaryotic Elongation Factor 2 (eEF2), the protein that mediates the movement of the ribosome along the mRNA by promoting translocation from the A to the P site. eEF2K-mediated phosphorylation of eEF2 on Thr56 decreases its affinity for the ribosome, thereby inhibiting elongation. Here we show that in response to genotoxic stress, eEF2K is activated by AMPK-mediated phosphorylation on Ser398. Activated eEF2K phosphorylates eEF2 and induces a temporary ribosomal slowdown at the stage of elongation. Subsequently, during checkpoint silencing, eEF2K is degraded by the ubiquitin-proteasome system via the SCFβTrCP ubiquitin ligase to allow rapid resumption of translation elongation. This event requires eEF2K autophosphorylation on a canonical βTrCP-binding domain. The inability to degrade eEF2K during checkpoint silencing caused sustained phosphorylation of eEF2 on Thr56 and delayed resumption of translation elongation. Our study establishes an important link between DNA damage signaling and translation elongation.

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