2026-03-23 ミュンヘン大学（LMU）
＜関連情報＞
- https://www.lmu.de/en/newsroom/news-overview/news/cells-under-stress-chemotherapy-drug-damages-rna-9af439f0.html
- https://www.cell.com/molecular-cell/fulltext/S1097-2765(26)00138-3
RNF25は統合ストレス応答の活性化を抑制することにより、mRNA損傷耐性を付与する RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response
Shubo Zhao ∙ Chloe S. Palma-Chaundler ∙ Carla M. Engel ∙ … ∙ Marion Subklewe ∙ Stephen P. Jackson ∙ Julian Stingele
Molecular Cell Published:March 23, 2026
DOI:https://doi.org/10.1016/j.molcel.2026.02.024
Graphical abstract
Highlights
- CRISPR screens reveal cellular networks responding to azacytidine treatment
- The integrated stress response (ISR) drives azacytidine-induced cytotoxicity
- Incorporation of azacytidine into mRNA causes ribosome stalling and ISR activation
- RNF25 prevents ISR activation by ubiquitylating the small ribosomal subunit
Summary
Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.
