Coupled activation and degradation of eEF2K regulates protein synthesis in response to genotoxic stress

Flore Kruiswijk, Laurensia Yuniati, Roberto Magliozzi, Teck Yew Low, Ratna Lim, Renske Bolder, Shabaz Mohammed, Christopher G. Proud, Albert J.R. Heck, Michele Pagano, Daniele Guardavaccaro

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)


The kinase eEF2K [eukaryotic elongation factor 2 (eEF2) kinase] controls the rate of peptide chain elongation by phosphorylating eEF2, the protein that mediates the movement of the ribosome along the mRNA by promoting translocation of the transfer RNA from the A to the P site in the ribosome. eEF2K-mediated phosphorylation of eEF2 on threonine 56 (Thr 56) decreases its affinity for the ribosome, thereby inhibiting elongation. Here, we show that in response to genotoxic stress, eEF2K was activated by AMPK (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eEF2K phosphorylated eEF2 and induced a temporary ribosomal slowdown at the stage of elongation. Subsequently, during DNA damage checkpoint silencing, a process required to allow cell cycle reentry, eEF2K was degraded by the ubiquitin-proteasome system through the ubiquitin ligase SCF βTrCP (Skp1-Cul1-F-box protein, β-transducin repeat-containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eEF2K on a canonical βTrCP-binding domain. The inability to degrade eEF2K during checkpoint silencing caused sustained phosphorylation of eEF2 on Thr 56 and delayed the resumption of translation elongation. Our study therefore establishes a link between DNA damage signaling and translation elongation.

Original languageEnglish
Article numberra40
JournalScience Signaling
Issue number227
Publication statusPublished or Issued - 5 Jun 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this