Journal Club

DNA damage induces p53-independent apoptosis through ribosome stalling

Science 2024

Editor’s summary

Effective anticancer therapies cause DNA damage and kill cancer cells through a p53-dependent mechanism, but they can also kill cancer cells in which p53 is mutated. Boon et al. elucidated a pathway by which DNA damage can induce cell death in cells lacking p53. In cultured human cells, apoptosis induced by DNA damage occurred in cells with decreased translation. A genetic screen showed that this response required the transfer RNA endonuclease SLFN11, which is often found to be mutated in cancers unresponsive to chemotherapy. Activation of SLFN11 led to ribosome stalling, which then signaled initiation of apoptosis.

Abstract

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 results provide an explanation for the frequent inactivation of SLFN11 in chemotherapy-unresponsive tumors and highlight ribosome stalling as a signaling event affecting cell fate in response to DNA damage.