title: Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in lung cancer cells.
abstract: Ran Binding Protein 9 (RanBP9, also known as RanBPM) is an evolutionary conserved scaffold protein present both in the nucleus and the cytoplasm of cells whose biological functions remain elusive. We show that active ATM phosphorylates RanBP9 on at least two different residues (S181 and S603). In response to IR, RanBP9 rapidly accumulates into the nucleus of lung cancer cells, but this nuclear accumulation is prevented by ATM inhibition. RanBP9 stable silencing in three different lung cancer cell lines significantly affects the DNA Damage Response (DDR), resulting in delayed activation of key components of the cellular response to IR such as ATM itself, Chk2, γH2AX, and p53. Accordingly, abrogation of RanBP9 expression reduces homologous recombination-dependent DNA repair efficiency, causing an abnormal activation of IR-induced senescence and apoptosis. In summary, here we report that RanBP9 is a novel mediator of the cellular DDR, whose accumulation into the nucleus upon IR is dependent on ATM kinase activity. RanBP9 absence hampers the molecular mechanisms leading to efficient repair of damaged DNA, resulting in enhanced sensitivity to genotoxic stress. These findings suggest that targeting RanBP9 might enhance lung cancer cell sensitivity to genotoxic anti-neoplastic treatment.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Dario
authors.initials: D
authors.lastname: Palmieri
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Scarpa
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Tessari
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Rexhep
authors.initials: R
authors.lastname: Uka
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Foued
authors.initials: F
authors.lastname: Amari
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Richmond
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Foray
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Sheetz
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Braddom
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Christin E
authors.initials: CE
authors.lastname: Burd
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Parvin
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA.|Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C116005:Ran binding protein 9; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; DNA damage; RanBP9; RanBPM; ionizing radiation