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RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [Ribo-seq]

ABSTRACT: 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 here 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, 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). RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, suppresses cell death upon azacytidine tretament. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313819 | GEO | 2026/03/23

REPOSITORIES: GEO

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RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response

Project description: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 here 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, 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). RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, suppresses 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.

2026-03-23 | GSE288321 | GEO

RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [TTchem-seq]

Project description: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 here 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, 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). RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, suppresses cell death upon azacytidine tretament. 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.

2026-03-23 | GSE314149 | GEO

RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [RNA-seq]

Project description: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 here 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, 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). RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, suppresses cell death upon azacytidine tretament. 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.

2026-03-23 | GSE313818 | GEO

RNF25 provides tolerance towards chemotherapeutic mRNA damage

Project description:Many chemotherapeutic agents damage DNA, which is believed to mediate their therapeutic efficacy. However, most of these agents act pleiotropically and also damage RNA, raising questions about the contribution of RNA damage to therapeutic outcomes and whether cells possess factors that protect them from chemotherapeutic RNA damage. In this project, we compare the cellular response to azacytidine (azaC) and decitabine (azadC), two nucleoside analogues that are used to treat acute myeloid leukemia (AML). We uncovered that 5azaC induces RNA damage and triggers cell death through the integrated stress response, which is mediated by GCN1 and GCN2. We also identified the ubiquitin E3 ligases RNF25 as a specific resistance factor to 5azaC treatment. Combining ubiquitylome and phospho-proteome, we explore the underlying cellular signalling associated with 5azaC sensitivity and resistance

2026-03-14 | PXD059287 | Pride

RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response

Project description:RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response

| PRJNA1216923 | ENA

RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [TTchem-seq]

Project description:RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [TTchem-seq]

| PRJNA1390168 | ENA

RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [RNA-seq]

Project description:RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [RNA-seq]

| PRJNA1381637 | ENA

RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [Ribo-seq]

Project description:RNF25 confers tolerance to azacytidine-induced mRNA damage by curbing activation of the integrated stress response [Ribo-seq]

| PRJNA1381639 | ENA

The E3 ubiquitin ligase RNF25 protects stalled DNA replication forks

Project description:Cancer cells experience high levels of replication stress and have therefore adapted mechanisms to tolerate replication stress. Using a CRISPR screen, we identified RNF25 as a mediator of replication stress tolerance in cancer cells. RNF25-ablation results in ssDNA accumulation, decreased replication fork movement, and increased replication fork degradation dependent on nucleases MRE11 and CtIP. To identify potential interactors of RNF25 in mediating replication stress tolerance, we performed mass-spectrometry analysis of immunopurified RNF25-complexes. We discovered REV7 as a novel binding partner of RNF25. REV7 was previously shown to protect replication forks in a Shieldin-independent but REV1- and REV3L-dependent manner. Further investigation revealed that RNF25 is also epistatic to REV1 and REV3L in a fork protection pathway and that REV7 recruitment to replication forks following stress is dependent on RNF25. Our findings establish a novel role of RNF25 in replication fork protection.

2025-06-30 | PXD056698 | Pride

RNF25-Mediated NF-κB Activation Drives Anti-Apoptosis and Therapy Resistance in Cancer

Project description:Dysregulation of the NF-κB pathway is frequently observed in cancers, contributing to therapy resistance by inhibiting apoptosis. In this study, we identify RNF25, an E3 ubiquitin ligase, as a key regulator of signal transduction, inflammation, immune responses, and apoptosis. RNA sequencing (RNA-seq) analysis following RNF25 knockdown revealed significant alterations in key apoptotic regulators and NF-κB signaling components, highlighting the role of RNF25 in apoptotic resistance and therapeutic response. Pathway enrichment analysis further demonstrated disruptions in pro-survival and inflammatory signaling pathways, suggesting that RNF25 knockdown enhances apoptotic sensitivity and may influence treatment efficacy. This dataset provides valuable insights into potential therapeutic targets for overcoming treatment resistance.

2025-03-25 | GSE291116 | GEO

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