title: Nrf1 CNC-bZIP protein promotes cell survival and nucleotide excision repair through maintaining glutathione homeostasis.
abstract: Skin cancer is the most common cancer in the United States. Its major environmental risk factor is UVB radiation in sunlight. In response to UVB damage, epidermal keratinocytes activate a specific repair pathway, i.e. nucleotide excision repair, to remove UVB-induced DNA lesions. However, the regulation of UVB response is not fully understood. Here we show that the long isoform of the nuclear factor erythroid 2-related factor 1 (Nrf1, also called NFE2L1), a cytoprotective transcription factor critical for the expression of multiple antioxidant response element-dependent genes, plays an important role in the response of keratinocytes to UVB. Nrf1 loss sensitized keratinocytes to UVB-induced apoptosis by up-regulating the expression of the proapoptotic Bcl-2 family member Bik through reducing glutathione levels. Knocking down Bik reduced UVB-induced apoptosis in Nrf1-inhibited cells. In UVB-irradiated surviving cells, however, disruption of Nrf1 impaired nucleotide excision repair through suppressing the transcription of xeroderma pigmentosum C (XPC), a factor essential for initiating the global genome nucleotide excision repair by recognizing the DNA lesion and recruiting downstream factors. Nrf1 enhanced XPC expression by increasing glutathione availability but was independent of the transcription repressor of XPC. Adding XPC or glutathione restored the DNA repair capacity in Nrf1-inhibited cells. Finally, we demonstrate that Nrf1 levels are significantly reduced by UVB radiation in mouse skin and are lower in human skin tumors than in normal skin. These results indicate a novel role of Nrf1 in UVB-induced DNA damage repair and suggest Nrf1 as a tumor suppressor in the skin.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Weinong
authors.initials: W
authors.lastname: Han
authors.forename: Mei
authors.initials: M
authors.lastname: Ming
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.forename: Chunli
authors.initials: C
authors.lastname: Wu
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
mesh_terms: D002470:Cell Survival; D004260:DNA Repair; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D051266:Nuclear Respiratory Factor 1 / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C105242:ALYREF protein, human; C495633:NRF1 protein, human; D009687:Nuclear Proteins; D051266:Nuclear Respiratory Factor 1; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D005978:Glutathione