DNA damage induces p53-independent apoptosis through ribosome stalling

In response to excessive DNA damage, human cells can activate p53 to induce apoptosis. Cells lacking p53 can still undergo apoptosis upon DNA damage, yet the responsible pathways are unknown. We observed that p53-independent apoptosis in response to DNA damage coincided with translation inhibition, which was characterized by ribosome stalling on rare leucine-encoding UUA codons and globally curtailed translation initiation. A genetic screen identified the transfer RNAse SLFN11 and the kinase GCN2 as factors required for UUA stalling and global translation inhibition, respectively. Stalled ribosomes activated a ribotoxic stress signal conveyed by the ribosome sensor ZAKα to the apoptosis machinery. These…

• BS
  Bristol-Myers Squibb
• H
  Health~Holland
• NR
  National Research Foundation
• DG
  Danmarks Grundforskningsfond
• MV
  Ministerie van Volksgezondheid, Welzijn en Sport
• NN
  Novo Nordisk
• OI
  Oncode Institute