The ribotoxic stress response drives UV-mediated cell death Journal Article
| Authors: | Sinha, N. K.; McKenney, C.; Yeow, Z. Y.; Li, J. J.; Nam, K. H.; Yaron-Barir, T. M.; Johnson, J. L.; Huntsman, E. M.; Cantley, L. C.; Ordureau, A.; Regot, S.; Green, R. |
| Article Title: | The ribotoxic stress response drives UV-mediated cell death |
| Abstract: | While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage. © 2024 The Authors |
| Keywords: | signal transduction; controlled study; protein phosphorylation; human cell; ultraviolet radiation; mass spectrometry; metabolism; cell death; dna damage; apoptosis; stress, physiological; signaling; protein degradation; protein serine threonine kinase; autophosphorylation; phosphorylation; proteomics; radiation response; immunoprecipitation; immunoblotting; dna damage response; high performance liquid chromatography; homeostasis; cellular stress response; ultraviolet rays; site directed mutagenesis; immunofluorescence microscopy; rna sequence; ribosomes; transcriptome sequencing; adverse event; ribosome; uv radiation; phosphoproteomics; physiological stress; humans; human; article; ultra performance liquid chromatography; immunofluorescence assay; gcn2; collisions; hek293t cell line; hek293-ft cell line; protein serine-threonine kinases; hacat cell line; ribotoxic stress; zak; mcf-10at cell line; ribotoxic stress response |
| Journal Title: | Cell |
| Volume: | 187 |
| Issue: | 14 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2024-07-11 |
| Start Page: | 3652 |
| End Page: | 3670.e40 |
| Language: | English |
| DOI: | 10.1016/j.cell.2024.05.018 |
| PUBMED: | 38843833 |
| PROVIDER: | scopus |
| PMCID: | PMC11246228 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Alban Ordureau -- Source: Scopus |
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