read_status: unread
type: paper
title: "DNA damage induces p53-independent apoptosis through ribosome stalling"
year: 2024
authors:
- "Boon, Nicolaas J."
- "Oliveira, Rafaela A."
- "Körner, Pierré-René"
- "Kochavi, Adva"
- "Mertens, Sander"
- "Malka, Yuval"
- "Voogd, Rhianne"
- "Van Der Horst, Suzanne E. M."
- "Huismans, Maarten A."
- "Smabers, Lidwien P."
- "Draper, Jonne M."
- "Wessels, Lodewyk F. A."
- "Haahr, Peter"
- "Roodhart, Jeanine M. L."
- "Schumacher, Ton N. M."
- "Snippert, Hugo J."
- "Agami, Reuven"
- "Brummelkamp, Thijn R."
journal: "Science"
doi: "10.1126/science.adh7950"
url: "https://www.science.org/doi/10.1126/science.adh7950"
project:
- IGP
system:
- cytosolic_ribosomes
- translation_machinery
- cancer_cells
- tumor_organoids
- primary_t_cells
disease:
- cancer
- chemotherapy_response
genes:
- slfn11
- gcn2
- zak
- eif2a
processes:
- ribosome_stalling
- tRNA_cleavage
- translation_initiation_inhibition
- ribotoxic_stress
- p53_independent_apoptosis
methods:
- ribosome_profiling
- haploid_genetic_screen
- puromycin_translation_assay
- diricore_codon_occupancy
- organoid_models
key_findings:
- slfn11_dependent_tRNA_uua_degradation
- codon_specific_ribosome_stalling
- gcn2_dependent_translation_shutdown
- zak_dependent_jnk_activation
- ribosome_stalling_driven_apoptosis
limitations:
- incomplete_upstream_dna_damage_sensing
- cell_type_specific_variability
- limited_non_genotoxic_contexts
relevance:
- mechanistic_link_between_dna_damage_and_translation
- biomarker_for_chemotherapy_sensitivity
- ribosome_as_signaling_platform
concepts:
- dna_damage_induced_ribosome_stalling
- ribotoxic_stress_response
- codon_specific_translation_control
- translation_apoptosis_coupling
tags:
- translation_control
- ribosome_signaling
- stress_response
- apoptosis
- cancer_therapy
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. , 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. —L. Bryan Ray
DNA damage induces global translation inhibition coupled to codon-specific ribosome stalling
Ribosomes stall selectively at rare leucine UUA codons
SLFN11 nuclease activity is required for UUA tRNA depletion and ribosome stalling
GCN2-mediated eIF2α phosphorylation drives global translation shutdown
ZAKα senses stalled ribosomes, activating JNK-dependent mitochondrial apoptosis
Apoptosis occurs independently of p53 and preferentially in low-translation cells
SLFN11 loss uncouples DNA damage from translation inhibition and apoptosis
Puromycin incorporation as single-cell translation readout
Haploid gene-trap mutagenesis screens for translation and apoptosis regulators
Ribosome profiling with Diricore codon occupancy analysis
Genetic knockouts and nuclease-dead SLFN11 rescue
Patient-derived tumor organoids and primary human T cells
Reframes DNA damage response to include ribosome-based signaling
Establishes codon usage as a stress-sensitive regulatory layer
Separates translation inhibition from apoptosis execution
Positions SLFN11 as a molecular switch between genotoxic stress and cell fate
Explains SLFN11 loss as a mechanism of chemotherapy resistance
Figure 1: DNA damage causes global translation inhibition and UUA-specific ribosome stalling
Figure 2: SLFN11 and GCN2 genetically required for stalling and translation shutdown
Figure 3: SLFN11-dependent, p53-independent apoptosis
Figure 4: ZAKα-mediated ribotoxic stress signaling to JNK
Figure 5: Conservation of mechanism in tumor organoids and primary T cells
Upstream sensing linking DNA lesions to SLFN11 activation unresolved
Partial translation inhibition persists in some knockout contexts
Limited exploration of non-cancer, non-genotoxic stress conditions