ArticleMolecular medicine (Cambridge, Mass.)2024
USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM.
Article in Molecular medicine (Cambridge, Mass.), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed.
- β-carboline derivative Z86 alleviates pulmonary fibrosis via suppressing TGF-β/Smad signaling.Natural products and bioprospecting · 2026Article
- Deubiquitinating enzymes in cervical cancer: Molecular mechanisms and therapeutic implications (Review).International journal of oncology · 2026Review
- Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review).International journal of molecular medicine · 2026Review
- Deubiquitinase USP15 restricts LC3-dependent targeting ofAutophagy · 2026Article
- Protective effects of mouse bone marrow mesenchymal stem cell-derived extracellular vesicles on radiation-induced epididymal cells damage via USP44/RBM14 axis.Stem cell research & therapy · 2025Article
- Mechanistic pathways predictive modeling and translational interventions for radiation enteritis in cervical cancer radiotherapy.Frontiers in cellular and infection microbiology · 2025Review
- Radiation-induced intestinal injury: from molecular mechanisms to clinical translation.Oncology reviews · 2025Review
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10 authors.
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Abstract
backgroundRadiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR). However, whether ATM is regulated by deubiquitination signaling remains unclear.
methodsWe established animal and cellular models of RIII. The effects of ubiquitin-specific protease 15 (USP15) on DNA damage and radion-induced intestinal injury were evaluated. Mass spectrometry analysis, truncation tests, and immunoprecipitation were used to identify USP15 as a binding partner of ATM and to investigate the ubiquitination of ATM. Finally, the relationship between the USP15/ATM axes was further determined via subsequent experiments.
resultsIn this study, we identified the deubiquitylating enzyme USP15 as a regulator of DNA damage and the pathological progression of RIII. Irradiation upregulates the expression of USP15, whereas pharmacological inhibition of USP15 exacerbates radiation-induced DNA damage and RIII both in vivo and in vitro. Mechanistically, USP15 interacts with, deubiquitinates, and stabilises ATM via K48-linked deubiquitination. Notably, ATM overexpression blocks the effect of USP15 genetic inhibition on DNA damage and RIII progression.
conclusionsThese findings describe ATM as a novel deubiquitination target of USP15 upon radiation-induced DNA damage and intestinal injury, and provides experimental support for USP15/ATM axis as a potential target for developing strategies that mitigate RIII.
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