RT Journal Article
SR Electronic
T1 Coupled Activation and Degradation of eEF2K Regulates Protein Synthesis in Response to Genotoxic Stress
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra40
OP ra40
DO 10.1126/scisignal.2002718
VO 5
IS 227
A1 Kruiswijk, Flore
A1 Yuniati, Laurensia
A1 Magliozzi, Roberto
A1 Low, Teck Yew
A1 Lim, Ratna
A1 Bolder, Renske
A1 Mohammed, Shabaz
A1 Proud, Christopher G.
A1 Heck, Albert J. R.
A1 Pagano, Michele
A1 Guardavaccaro, Daniele
YR 2012
UL http://stke.sciencemag.org/content/5/227/ra40.abstract
AB 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 (Thr56) 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 SCFβTrCP (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 Thr56 and delayed the resumption of translation elongation. Our study therefore establishes a link between DNA damage signaling and translation elongation.