DNA damage induces p53-independent apoptosis through ribosome stalling

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,...

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Published in:Science (American Association for the Advancement of Science) 2024-05, Vol.384 (6697), p.785-792
Main 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
Format: Article
Language:English
Subjects:
Apoptosis
Cell death
Cell Line, Tumor
Chemotherapy
Codon - genetics
Damage
Deoxyribonucleic acid
DNA
DNA Damage
Endonuclease
Genetic screening
Humans
Leucine - genetics
MAP Kinase Kinase Kinases - genetics
MAP Kinase Kinase Kinases - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
p53 Protein
Protein Biosynthesis
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Ribosomes - metabolism
Signal Transduction
Stalling
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.adh7950