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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Science |
| Vol/bind | 384 |
| Udgave nummer | 6697 |
| Sider (fra-til) | 785-792 |
| Antal sider | 8 |
| ISSN | 0036-8075 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:We thank P. Borst, T. Sixma, P. Knipscheer, and members of the Brummelkamp lab for helpful discussions and critical reading of our manuscript and the Flow Cytometry and Genomics Core facility at Netherlands Cancer Institute for experimental support. This work was supported by an institutional grant of the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport, Oncode Institute, European Research Council (ERC-AdG grant 832844) and Health-Holland (LSH-TKI grant LSHM19058). P.H. was supported by the Novo Nordisk Foundation and the Danish National Research Foundation (grant DNRF-166). L.W. received funding from Bristol Myers Squibb.
Funding Information:
We thank P. Borst, T. Sixma, P. Knipscheer, and members of the Brummelkamp lab for helpful discussions and critical reading of our manuscript and the Flow Cytometry and Genomics Core facility at Netherlands Cancer Institute for experimental support. Funding: This work was supported by an institutional grant of the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport, Oncode Institute, European Research Council (ERC-AdG grant 832844) and Health-Holland (LSH-TKI grant LSHM19058). P.H. was supported by the Novo Nordisk Foundation and the Danish National Research Foundation (grant DNRF-166). L.W. received funding from Bristol Myers Squibb. Author contributions: Conceptualization: N.J.B., R.A., T.R.B.; Investigation and data analysis: N.J.B., R.A.O., A.K., S.M., Y.M., S.E.M.v.d.H., J.M.D., P.H., P.R.K.; Methodology: N.J.B., R.A.O., H.J.S., P.H., L.F.A.W., R.A., T.R.B., T.N.M.S.; Organoid or T-cell generation: R.V., L.P.S., M.A.H., J.M.L.R.; Supervision: T.R.B., R.A.; Visualization: N.J.B., T.R.B., P.H., R.A.; Writing \u2013 original draft: N.J.B., T.R.B.; Writing \u2013 review & editing: N.J.B., T.R.B., P.H., R.A. Competing interests: T.R.B. is a cofounder and scientific advisory board member of Scenic Biotech. The remaining authors declare no competing interests. Data and materials availability: Correspondence and requests for materials should be addressed to R.A. and T.R.B. HAP1 cells are available from the Netherlands Cancer Institute under a material transfer agreement with that institution. Sequencing data and screening data are available, respectively, at the NCBI Sequence Read Archive (www.ncbi.nlm.nih.gov/sra/PRJNA1082660) and an interactive visualization platform (https://phenosaurus.nki.nl/). License information: Copyright \u00A9 2024 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/science-licenses-journal-article-reuse
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