title: Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair.
abstract: Histone demethylases have recently gained interest as potential targets in cancer treatment and several histone demethylases have been implicated in the DNA damage response. We investigated the effects of siRNA-mediated depletion of histone demethylase Jarid1A (KDM5A, RBP2), which demethylates transcription activating tri- and dimethylated lysine 4 at histone H3 (H3K4me3/me2), on growth characteristics and cellular response to radiation in several cancer cell lines. In unirradiated cells Jarid1A depletion lead to histone hyperacetylation while not affecting cell growth. In irradiated cells, depletion of Jarid1A significantly increased cellular radiosensitivity. Unexpectedly, the hyperacetylation phenotype did not lead to disturbed accumulation of DNA damage response and repair factors 53BP1, BRCA1, or Rad51 at damage sites, nor did it influence resolution of radiation-induced foci or rejoining of reporter constructs. We conclude that the radiation sensitivity observed following depletion of Jarid1A is not caused by a deficiency in repair of DNA double-strand breaks.
authors.affiliation: Department of Radiation Oncology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Penterling
authors.affiliation: Department of Radiation Oncology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Guido A
authors.initials: GA
authors.lastname: Drexler
authors.affiliation: Department of Radiation Oncology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Böhland
authors.affiliation: Department of Radiation Oncology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Stamp
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Wilke
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Braselmann
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Randolph B
authors.initials: RB
authors.lastname: Caldwell
authors.affiliation: Institut für Angewandte Physik und Messtechnik, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Reindl
authors.affiliation: Institut für Angewandte Physik und Messtechnik, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Girst
authors.affiliation: Institut für Angewandte Physik und Messtechnik, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Greubel
authors.affiliation: Department of Radiation Oncology, Technical University of Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Siebenwirth
authors.affiliation: Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Tumor Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Wael Y
authors.initials: WY
authors.lastname: Mansour
authors.affiliation: Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Borgmann
authors.affiliation: Institut für Angewandte Physik und Messtechnik, Universität der Bundeswehr München, Neubiberg, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Dollinger
authors.affiliation: Research Unit Radiation Cytogenetics, Helmholtz Center Munich, Neuherberg, Germany.|Clinical Cooperation Group 'Personalized Radiotherapy of Head and Neck Cancer', Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Unger
authors.affiliation: Department of Radiation Oncology, Ludwig-Maximilians-University of Munich, Munich, Germany.|Clinical Cooperation Group 'Personalized Radiotherapy of Head and Neck Cancer', Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Friedl
mesh_terms: D000107:Acetylation; D049109:Cell Proliferation / Q000528:radiation effects; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D010957:Plasmids / Q000378:metabolism; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D056485:Retinoblastoma-Binding Protein 2 / Q000378:metabolism*
chemical_list: D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; D008239:Lysine