USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM
Abstract Background Radiation-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 biol...
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BMC
2024-11-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-024-00984-8 |
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| author | Ruiqiu Zhu Mingyue Li Difan Wang Chengzhi Liu Liwei Xie Yinyin Yang Xuhao Gu Kui Zhao Ye Tian Shang Cai |
| author_facet | Ruiqiu Zhu Mingyue Li Difan Wang Chengzhi Liu Liwei Xie Yinyin Yang Xuhao Gu Kui Zhao Ye Tian Shang Cai |
| author_sort | Ruiqiu Zhu |
| collection | DOAJ |
| description | Abstract Background Radiation-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. Methods We 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. Results In 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. Conclusions These 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. |
| format | Article |
| id | doaj-art-966b0e265d814b8fa2708fda4809fbbd |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-966b0e265d814b8fa2708fda4809fbbd2024-11-10T12:30:12ZengBMCMolecular Medicine1528-36582024-11-0130111710.1186/s10020-024-00984-8USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATMRuiqiu Zhu0Mingyue Li1Difan Wang2Chengzhi Liu3Liwei Xie4Yinyin Yang5Xuhao Gu6Kui Zhao7Ye Tian8Shang Cai9Suzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversitySuzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversitySuzhou Medical College of Soochow UniversitySuzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversitySuzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversitySuzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversitySuzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversityDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow UniversitySuzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversitySuzhou Key Laboratory for Radiation Oncology, Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow UniversityAbstract Background Radiation-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. Methods We 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. Results In 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. Conclusions These 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.https://doi.org/10.1186/s10020-024-00984-8Radiation-induced intestinal injuryDNA damage responseDeubiquitinationUSP15ATM |
| spellingShingle | Ruiqiu Zhu Mingyue Li Difan Wang Chengzhi Liu Liwei Xie Yinyin Yang Xuhao Gu Kui Zhao Ye Tian Shang Cai USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM Molecular Medicine Radiation-induced intestinal injury DNA damage response Deubiquitination USP15 ATM |
| title | USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM |
| title_full | USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM |
| title_fullStr | USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM |
| title_full_unstemmed | USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM |
| title_short | USP15 regulates radiation-induced DNA damage and intestinal injury through K48-linked deubiquitination and stabilisation of ATM |
| title_sort | usp15 regulates radiation induced dna damage and intestinal injury through k48 linked deubiquitination and stabilisation of atm |
| topic | Radiation-induced intestinal injury DNA damage response Deubiquitination USP15 ATM |
| url | https://doi.org/10.1186/s10020-024-00984-8 |
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