AI Article Synopsis
- Human cells can trigger a form of programmed cell death (apoptosis) when faced with DNA damage, primarily through the activation of the p53 protein.
- Interestingly, even cells without p53 can still undergo apoptosis, which seems to be linked to issues with protein translation, specifically ribosomes stalling on rare codons and reduced translation initiation.
- A genetic study revealed that the tRNAse SLFN11 and the kinase GCN2 are crucial for this stalling and subsequent stress signaling, which leads to apoptosis, offering insights into chemotherapy resistance in certain tumors where SLFN11 is often inactive.
Article 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.
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| http://dx.doi.org/10.1126/science.adh7950 | DOI Listing |
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