UV radiation not only induces DNA damage, but also damages RNA, eliciting a ribotoxic stress response (RSR), but its contribution to subsequent cell death remains unclear. Green and colleagues establish a detailed timeline of signalling events activated in cells upon UV damage and report that UV-mediated apoptosis is driven by RSR, and not the DNA damage response.

The authors show that the immediate-early UV radiation response is dominated by ribosome-mediated signalling with activation of the RSR kinases ZAK and GCN2, and subsequent cell death; this is driven by RSR as inhibition of ZAK, but not of the DNA damage response, prior to radiating cells prevents apoptosis. They then explore the role of GCN2 and find that its activation limits ribosomal collisions, attenuating ZAK and resolving ribotoxic stress. Furthermore, ZAK activation results in its autophosphorylation and subsequent degradation, which, in turn, restricts apoptosis to enable tolerance under persistent ribotoxic stress.