The p53 protein is a key transcription factor responsible for inducing apoptosis in response to DNA damage, such as damage induced by chemotherapeutics. However, cells with an impaired p53 pathway can still undergo apoptosis, suggesting the existence of alternative p53-independent apoptosis pathways in these cells. Boon et al. have now identified such a pathway, in which ribosomes stall on the rare leucine codon UUA in response to DNA damage, resulting in ribotoxic stress and subsequent activation of apoptosis.

The team showed that etoposide, a chemotherapy medication, induced apoptosis along with a global decrease in protein synthesis in cells with p53 knocked out. Ribosome-profiling assays showed that ribosome stalling occurred both at the translation start site and on the rare UUA codon in response to etoposide-induced DNA damage. Through a genetic mutagenesis screen, the team identified two key genes that affect translation in response to etoposide treatment: SLFN11 and GCN2 (also known as EIF2AK4).