title: Radioprotective effects of Bmi-1 involve epigenetic silencing of oxidase genes and enhanced DNA repair in normal human keratinocytes.
abstract: Normal human keratinocytes (NHKs) undergo premature senescence following exposure to ionizing radiation (IR). This study investigates the effect of Bmi-1, a polycomb group protein, on radiation-induced senescence response. When exposed to IR, NHK transduced with Bmi-1 (NHK/Bmi-1) showed reduced senescent phenotype and enhanced proliferation compared with control cells (NHK/B0). To investigate the underlying mechanism, we determined the production of reactive oxygen species (ROS), expression of ROS-generating enzymes, and DNA repair activities in cells. ROS level was increased upon irradiation but notably reduced by Bmi-1 transduction. Irradiation led to strong induction of oxidase genes, e.g., Lpo (lactoperoxidase), p22-phox, p47-phox, and Gp91, in NHK/B0 but their expression was almost completely silenced in NHK/Bmi-1. Induction of oxidase genes upon irradiation was linked with loss of trimethylated histone 3 at lysine 27 (H3K27Me3), but NHK/Bmi-1 expressed a higher level of H3K27Me3 compared with NHK/B0. Bmi-1 transduction suppressed IR-associated induction of jumanji domain containing 3 while enhancing the expression of EZH2, thereby preventing the loss of H3K27Me3 in the irradiated cells. Furthermore, NHK/Bmi-1 demonstrated increased repair of IR-induced DNA damage compared with NHK/B0. These results indicate that Bmi-1 elicits radioprotective effects on NHK by mitigating the genotoxicity of IR through epigenetic mechanisms.
authors.affiliation: UCLA School of Dentistry, Center for the Health Sciences, Los Angeles, California 90095, USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Dong
authors.forename: Ju-Eun
authors.initials: JE
authors.lastname: Oh
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Roy
authors.initials: R
authors.lastname: Kim
authors.forename: Reuben H
authors.initials: RH
authors.lastname: Kim
authors.forename: Ki-Hyuk
authors.initials: KH
authors.lastname: Shin
authors.forename: William H
authors.initials: WH
authors.lastname: McBride
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence; D004260:DNA Repair; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects*; D009687:Nuclear Proteins / Q000502:physiology*; D010088:Oxidoreductases / Q000235:genetics*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011832:Radiation Injuries / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: C069077:BMI1 protein, human; D006657:Histones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D010088:Oxidoreductases; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D063150:Polycomb Repressive Complex 1