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Emerging evidence has suggested that NRF2 protects cells against DNA damage by mechanisms other than antioxidation, yet the mechanism remains poorly understood. Here, we demonstrate that knockout of NRF2 in cells results in hypersensitivity to ionizing radiation (IR) in the presence or absence of reactive oxygen species (ROS). Under ROS scavenging conditions, induction of DNA double-strand breaks (DSBs) increases the NRF2 protein level and recruits NRF2 to DNA damage sites where it interacts with ATR, resulting in activation of the ATR\u2013CHK1\u2013CDC2 signaling pathway. In turn, this leads to G2 cell cycle arrest and the promotion of homologous recombination repair of DSBs, thereby preserving genome stability. The inhibition of NRF2 by brusatol increased the radiosensitivity of tumor cells in xenografts by perturbing ATR and CHK1 activation. Collectively, our results reveal a novel function of NRF2 as an ATR activator in the regulation of the cellular response to DSBs. This shift in perspective should help furnish a more complete understanding of the function of NRF2 and the DNA damage response.<\/jats:p>","DOI":"10.1093\/nar\/gkaa631","type":"journal-article","created":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T19:24:12Z","timestamp":1595877852000},"page":"9109-9123","source":"Crossref","is-referenced-by-count":97,"title":["NRF2 preserves genomic integrity by facilitating ATR activation and G2 cell cycle arrest"],"prefix":"10.1093","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8218-1885","authenticated-orcid":false,"given":"Xiaohui","family":"Sun","sequence":"first","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihua","family":"Ji","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Kong","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Nie","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiu","family":"Hao","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3354-2386","authenticated-orcid":false,"given":"Chang","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqing","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,30]]},"reference":[{"key":"2020091720045763700_B1","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature"},{"key":"2020091720045763700_B2","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.molcel.2012.07.029","article-title":"Playing the end game: DNA double-strand break repair 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