title: PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function.
abstract: PALB2/FANCN is mutated in breast and pancreatic cancers and Fanconi anemia (FA). It controls the intranuclear localization, stability, and DNA repair function of BRCA2 and links BRCA1 and BRCA2 in DNA homologous recombination repair and breast cancer suppression. Here, we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NRF2. PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding. PALB2 promotes NRF2 accumulation and function in the nucleus and lowers the cellular reactive oxygen species (ROS) level. In addition, PALB2 also regulates the rate of NRF2 export from the nucleus following induction. Our findings identify PALB2 as a regulator of cellular redox homeostasis and provide a new link between oxidative stress and the development of cancer and FA.
authors.affiliation: Department of Radiation Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.
authors.forename: Jianglin
authors.initials: J
authors.lastname: Ma
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.forename: Bijan
authors.initials: B
authors.lastname: Sobhian
authors.forename: Yanying
authors.initials: Y
authors.lastname: Huo
authors.forename: Allen
authors.initials: A
authors.lastname: Alcivar
authors.forename: Monal
authors.initials: M
authors.lastname: Mehta
authors.forename: Ka Lung
authors.initials: KL
authors.lastname: Cheung
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004260:DNA Repair; D000076164:Fanconi Anemia Complementation Group N Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins