title: Distinct Role of Sesn2 in Response to UVB-Induced DNA Damage and UVA-Induced Oxidative Stress in Melanocytes.
abstract: Ultraviolet (UV) radiation, including both UVB and UVA irradiation, is the major risk factor for causing skin cancer including melanoma. Recently, we have shown that Sesn2, a member of the evolutionarily conserved stress-inducible protein family Sestrins (Sesn), is upregulated in human melanomas as compared to melanocytes in normal human skin, suggesting an oncogenic role of Sesn2. However, the role of Sesn2 in UVB and UVA response is unknown. Here, we demonstrated that both UVB and UVA induce Sesn2 upregulation in melanocytes and melanoma cells. UVB induces Sesn2 expression through the p53 and AKT3 pathways. Sesn2 negatively regulates UVB-induced DNA damage repair. In comparison, UVA induces Sesn2 upregulation through mitochondria but not Nrf2. Sesn2 ablation increased UVA-induced Nrf2 induction and inhibits UVA-induced ROS production, indicating that Sesn2 acts as an upstream regulator of Nrf2. These findings suggest previously unrecognized mechanisms in melanocyte response to UVB and UVA irradiation and potentially in melanoma formation.
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL.
authors.forename: Baozhong
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL.
authors.forename: Palak
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Orthopaedic Surgery & Rehabilitation Medicine, University of Chicago, Chicago, IL.
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.affiliation: Department of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Budanov
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000528:radiation effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation; D000084622:Sestrins
chemical_list: D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C495635:NFE2L2 protein, human; C465398:SESN2 protein, human; D000084622:Sestrins