Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence
Oxidative stress, driven by reactive oxygen species (ROS) such as hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), induces DNA double-strand breaks (DSBs) that compromise genomic integrity. The DNA Damage Response (DDR), primarily mediated by ATM and ATR kinases, is crucial fo...
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MDPI AG
2024-10-01
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| Series: | Antioxidants |
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| author | Mingyang Li Genbao Shao |
| author_facet | Mingyang Li Genbao Shao |
| author_sort | Mingyang Li |
| collection | DOAJ |
| description | Oxidative stress, driven by reactive oxygen species (ROS) such as hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), induces DNA double-strand breaks (DSBs) that compromise genomic integrity. The DNA Damage Response (DDR), primarily mediated by ATM and ATR kinases, is crucial for recognizing and repairing DSBs. Senataxin (SETX), a DNA/RNA helicase, is critical in resolving R-loops, with mutations in <i>SETX</i> associated with neurodegenerative diseases. This study uncovers a novel function of senataxin in modulating DDR and its impact on cellular senescence. Senataxin is shown to be crucial not only for DSB repair but also for determining cell fate under oxidative stress. <i>SETX</i> knockout cells show impaired DSB repair and prolonged ATM/ATR signaling detected by Western blotting, leading to increased senescence, as indicated by elevated β-galactosidase activity following H<sub>2</sub>O<sub>2</sub> exposure and I-PpoI-induced DSBs. Wild-type cells exhibit higher apoptosis levels compared to <i>SETX</i> knockout cells under H<sub>2</sub>O<sub>2</sub> treatment, suggesting that senataxin promotes apoptosis over senescence in oxidative stress. This indicates that senataxin plays a protective role against the accumulation of senescent cells, potentially mitigating age-related cellular decline and neurodegenerative disease progression. These findings highlight senataxin as a critical mediator in DDR pathways and a potential therapeutic target for conditions where cellular senescence contributes to disease pathology. |
| format | Article |
| id | doaj-art-4a3a3576e52f443cbe3da40b2db3e55a |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj-art-4a3a3576e52f443cbe3da40b2db3e55a2025-08-20T02:26:45ZengMDPI AGAntioxidants2076-39212024-10-011311133710.3390/antiox13111337Senataxin Attenuates DNA Damage Response Activation and Suppresses SenescenceMingyang Li0Genbao Shao1Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, ChinaDepartment of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, ChinaOxidative stress, driven by reactive oxygen species (ROS) such as hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), induces DNA double-strand breaks (DSBs) that compromise genomic integrity. The DNA Damage Response (DDR), primarily mediated by ATM and ATR kinases, is crucial for recognizing and repairing DSBs. Senataxin (SETX), a DNA/RNA helicase, is critical in resolving R-loops, with mutations in <i>SETX</i> associated with neurodegenerative diseases. This study uncovers a novel function of senataxin in modulating DDR and its impact on cellular senescence. Senataxin is shown to be crucial not only for DSB repair but also for determining cell fate under oxidative stress. <i>SETX</i> knockout cells show impaired DSB repair and prolonged ATM/ATR signaling detected by Western blotting, leading to increased senescence, as indicated by elevated β-galactosidase activity following H<sub>2</sub>O<sub>2</sub> exposure and I-PpoI-induced DSBs. Wild-type cells exhibit higher apoptosis levels compared to <i>SETX</i> knockout cells under H<sub>2</sub>O<sub>2</sub> treatment, suggesting that senataxin promotes apoptosis over senescence in oxidative stress. This indicates that senataxin plays a protective role against the accumulation of senescent cells, potentially mitigating age-related cellular decline and neurodegenerative disease progression. These findings highlight senataxin as a critical mediator in DDR pathways and a potential therapeutic target for conditions where cellular senescence contributes to disease pathology.https://www.mdpi.com/2076-3921/13/11/1337oxidative stresssenataxinSETXDNA double-strand break repairsenescenceDNA damage response |
| spellingShingle | Mingyang Li Genbao Shao Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence Antioxidants oxidative stress senataxin SETX DNA double-strand break repair senescence DNA damage response |
| title | Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence |
| title_full | Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence |
| title_fullStr | Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence |
| title_full_unstemmed | Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence |
| title_short | Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence |
| title_sort | senataxin attenuates dna damage response activation and suppresses senescence |
| topic | oxidative stress senataxin SETX DNA double-strand break repair senescence DNA damage response |
| url | https://www.mdpi.com/2076-3921/13/11/1337 |
| work_keys_str_mv | AT mingyangli senataxinattenuatesdnadamageresponseactivationandsuppressessenescence AT genbaoshao senataxinattenuatesdnadamageresponseactivationandsuppressessenescence |