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).

p53 蛋白是一种关键转录因子，负责诱导细胞凋亡以响应 DNA 损伤，例如化疗引起的损伤。然而，p53 途径受损的细胞仍然可以发生凋亡，这表明这些细胞中存在替代的 p53 独立凋亡途径。布恩等人。现在已经确定了这样一条途径，其中核糖体在罕见的亮氨酸密码子 UUA 上停滞以响应 DNA 损伤，导致核糖毒性应激并随后激活细胞凋亡。

研究小组表明，依托泊苷（一种化疗药物）可诱导细胞凋亡，同时 p53 敲除细胞中蛋白质合成全面减少。核糖体分析分析表明，在依托泊苷诱导的 DNA 损伤中，核糖体停滞发生在翻译起始位点和罕见的 UUA 密码子上。通过基因突变筛选，研究小组确定了两个影响依托泊苷治疗翻译的关键基因：SLFN11 和 GCN2（也称为 EIF2AK4）。