DNA damage induces p53-independent apoptosis through ribosome stalling

• 成果类型: Article
• 署名作者: Boon, Nicolaas J.; Oliveira, Rafaela A.; Koerner, Pierre-Rene; 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.
• 署名单位: Netherlands Cancer Institute; Netherlands Cancer Institute; Utrecht University; Utrecht University Medical Center; Netherlands Cancer Institute; Utrecht University; Utrecht University Medical Center; Netherlands Cancer Institute; University of Copenhagen
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9985
• DOI: 10.1126/science.adh7950
• 发表日期: 2024-05-17
• 页码: 785-792
• 关键词: transfer-rna-binding; cyclic gmp-amp; stress responses; cancer; gcn2; p53; sensitivity; activation; interacts; moiety

摘要

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 ZAK alpha 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.