NRF2 preserves genomic integrity by facilitating ATR activation and G2 cell cycle arrest.

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) is a well-characterized transcription factor that protects cells against oxidative and electrophilic stresses. 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-CHK1-CDC2 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.

• Authors: Xiaohui Sun, Yan Wang, Kaihua Ji, Yang Liu, Yangyang Kong, Shasha Nie, Na Li, Jianxiu Hao, Yi Xie, Chang Xu, Liqing Du, Qiang Liu
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 48 Issue 16 Pg. 9109-9123 (09 18 2020) ISSN: 1362-4962 [Electronic] England
• PMID: 32729622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Quassins
• brusatol
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1
• CDC2 Protein Kinase
• CDK1 protein, human

Topics

• A549 Cells
• Animals
• Ataxia Telangiectasia Mutated Proteins (genetics)
• CDC2 Protein Kinase (genetics)
• Carcinoma, Non-Small-Cell Lung (genetics, pathology, radiotherapy)
• Checkpoint Kinase 1 (genetics)
• DNA Breaks, Double-Stranded (drug effects, radiation effects)
• DNA Damage (drug effects, radiation effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Knockout Techniques
• Heterografts
• Humans
• Mice
• NF-E2-Related Factor 2 (genetics)
• Quassins (pharmacology)
• Radiation Tolerance (drug effects)
• Radiation, Ionizing
• Recombinational DNA Repair (drug effects, genetics, radiation effects)
• Signal Transduction (drug effects)