Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients
Abstract Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐a...
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505891 |
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| _version_ | 1849761767446544384 |
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| author | Tina Gruosso Virginie Mieulet Melissa Cardon Brigitte Bourachot Yann Kieffer Flavien Devun Thierry Dubois Marie Dutreix Anne Vincent‐Salomon Kyle Malcolm Miller Fatima Mechta‐Grigoriou |
| author_facet | Tina Gruosso Virginie Mieulet Melissa Cardon Brigitte Bourachot Yann Kieffer Flavien Devun Thierry Dubois Marie Dutreix Anne Vincent‐Salomon Kyle Malcolm Miller Fatima Mechta‐Grigoriou |
| author_sort | Tina Gruosso |
| collection | DOAJ |
| description | Abstract Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS‐mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple‐Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS‐mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients. |
| format | Article |
| id | doaj-art-6de217d98be14d7bb17cccccd1b794cc |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-6de217d98be14d7bb17cccccd1b794cc2025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-03-018552754910.15252/emmm.201505891Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patientsTina Gruosso0Virginie Mieulet1Melissa Cardon2Brigitte Bourachot3Yann Kieffer4Flavien Devun5Thierry Dubois6Marie Dutreix7Anne Vincent‐Salomon8Kyle Malcolm Miller9Fatima Mechta‐Grigoriou10Stress and Cancer Laboratory, Equipe Labelisée LNCC, Institut CurieStress and Cancer Laboratory, Equipe Labelisée LNCC, Institut CurieStress and Cancer Laboratory, Equipe Labelisée LNCC, Institut CurieStress and Cancer Laboratory, Equipe Labelisée LNCC, Institut CurieStress and Cancer Laboratory, Equipe Labelisée LNCC, Institut CurieInstitut Curie, CNRS UMR3347, INSERM U1021, University Paris‐Sud 11Department of Translational Research, Institut CurieInstitut Curie, CNRS UMR3347, INSERM U1021, University Paris‐Sud 11Department of Tumour Biology, Institut CurieDepartment of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at AustinStress and Cancer Laboratory, Equipe Labelisée LNCC, Institut CurieAbstract Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS‐mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple‐Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS‐mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.https://doi.org/10.15252/emmm.201505891JUNDNRF2RNF168Triple‐Negative breast cancerubiquitination |
| spellingShingle | Tina Gruosso Virginie Mieulet Melissa Cardon Brigitte Bourachot Yann Kieffer Flavien Devun Thierry Dubois Marie Dutreix Anne Vincent‐Salomon Kyle Malcolm Miller Fatima Mechta‐Grigoriou Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients EMBO Molecular Medicine JUND NRF2 RNF168 Triple‐Negative breast cancer ubiquitination |
| title | Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients |
| title_full | Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients |
| title_fullStr | Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients |
| title_full_unstemmed | Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients |
| title_short | Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients |
| title_sort | chronic oxidative stress promotes h2ax protein degradation and enhances chemosensitivity in breast cancer patients |
| topic | JUND NRF2 RNF168 Triple‐Negative breast cancer ubiquitination |
| url | https://doi.org/10.15252/emmm.201505891 |
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